“According to the World Health Organization, the cases of death caused by cancer will have been doubled until the year 2030. By 2010, cancer is expected to be the number one cause of death. Therefore, it is necessary to explore novel approaches for the treatment of cancer. Over past years, the antitumorigenic effects of cannabinoids have emerged as an exciting field in cancer research. Apart from their proapoptotic and antiproliferative action, recent research has shown that cannabinoids may likewise affect tumor cell angiogenesis, migration, invasion, adhesion, and metastasization…”

 

Cannabinoids in health and disease

“..the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, Alzheimer’s disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable…” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202504/

Stay ware!

Ware | Definition of ware by Merriam-Webster ( 😉 )

Please don’t tell me that there just hasn’t been enough research or that there just isn’t any science or studies backing up the use of cannabis for cancer. Please don’t tell me that we just just don’t know enough yet,,, ,,,stop the madness. End the genocide.
…let the CannaFangledAbstract InfoMediaBomb begin.

Cannabis in cancer care.

“Cannabis has been used in medicine for thousands of years prior to achieving its current illicit substance status. Cannabinoids, the active components of Cannabis sativa, mimic the effects of the endogenous cannabinoids (endocannabinoids), activating specific cannabinoid receptors, particularly CB1 found predominantly in the central nervous system and CB2 found predominantly in cells involved with immune function. Delta-9-tetrahydrocannabinol, the main bioactive cannabinoid in the plant, has been available as a prescription medication approved for treatment of cancer chemotherapy-induced nausea and vomiting and anorexia associated with the AIDS wasting syndrome. Cannabinoids may be of benefit in the treatment of cancer-related pain, possibly synergistic with opioid analgesics. Cannabinoids have been shown to be of benefit in the treatment of HIV-related peripheral neuropathy, suggesting that they may be worthy of study in patients with other neuropathic symptoms. Cannabinoids have a favorable drug safety profile,” http://www.ncbi.nlm.nih.gov/pubmed/25777363

 

Nature’s Answer For Cancer,  

Rick Simpson 

When Rick Simpson contacted the Canadian Cancer Society about hemp oil curing cancer. This was their response: “The society does not endorse or support medical products or dietary supplements. Thanks for the information. Good luck in your work.”

 

Run From the Cure – The Rick Simpson Story (Full)

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The Antitumor Activity of Plant-Derived Non-Psychoactive cannabinoids.

As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), Δ9-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment. http://www.ncbi.nlm.nih.gov/pubmed/25916739

Differential role of cannabinoids in the pathogenesis of skin of skin cancer.

“Cannabinoids (CB) like ∆9-tetrahydrocannabinol (THC) can induce cancer cell apoptosis and inhibit angiogenesis” http://www.ncbi.nlm.nih.gov/pubmed/25921771

Modulation of the tumor microenvironment and inhibition of EGF/EGFE pathway: novel anti-tumor mechanisms of Cannabidiol in Breast cancer.

“In summary, our study shows -for the first time-that CBD inhibits breast cancer growth and metastasis through novel mechanisms by inhibiting EGF/EGFR signaling and modulating the tumor microenvironment. These results also indicate that CBD can be used as a novel therapeutic option to inhibit growth and metastasis of highly aggressive breast cancer subtypes including TNBC, which currently have limited therapeutic options and are associated with poor prognosis and low survival rates.” http://www.ncbi.nlm.nih.gov/pubmed/25660577

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Tree of Life by The Human Revolution – Song about the remarkable Hemp Plant Cannabis sativa

“Tree of Life, winner of 2007 Marijuana Music Awards Best Music Video!
An educational music video about the many industrial uses and health benefits of the American Hemp plant. Featuring the song “Tree of Life” by Human of the band The Human Revolution.
http://www.thehumanrevolution.org/
Cannabis sativa “hemp” can benefit all of mankind.
It is #1 for: fiber, paper, food, oil, medicine and fuel.”

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Exploiting Cannabinoid-Induced Cytotoxic Autophagy to Drive Melanoma Cell Death.

“Although the global incidence of cutaneous melanoma is increasing, survival rates for patients with metastatic disease remain <10%.”
“Treatment with Δ9-Tetrahydrocannabinol (THC) resulted in the activation of autophagy, loss of cell viability, and activation of apoptosis, whereas cotreatment with chloroquine or knockdown of Atg7, but not Beclin-1 or Ambra1, prevented THC-induced autophagy and cell death in vitro. Administration of Sativex-like (a laboratory preparation comprising equal amounts of THC and cannabidiol (CBD)) to mice bearing BRAF wild-type melanoma xenografts substantially inhibited melanoma viability, proliferation, and tumor growth paralleled by an increase in autophagy and apoptosis compared with standard single-agent temozolomide. Collectively, our findings suggest that THC activates noncanonical autophagy-mediated apoptosis of melanoma cells,..” http://www.ncbi.nlm.nih.gov/pubmed/25674907

“Triple-negative breast cancer (TNBC) represents a subtype of breast cancer characterized by high aggressiveness. There is no current targeted therapy for these patients whose prognosis, as a group, is very poor. “
“The dual concept quinone/cannabinoid was supported by the fact that compound 10 exerts antitumor effect by inducing cell apoptosis through activation of CB2 receptors and through oxidative stress. Notably, it did not show either cytotoxicity on non-cancerous human mammary epithelial cells nor toxic effects in vivo suggesting that it may be a new therapeutic tool for the management of TNBC.” http://www.ncbi.nlm.nih.gov/pubmed/25671648

Δ9 -tetrahydrocannabinol and cannabidiol as potential curative agents for cancer. A critical examination of the preclinical literature.

“There is more support for an intratumoural route of administration of higher doses of Δ9 -THC. CBD produces effects in relevant concentrations and models, although more data are needed concerning its use in conjunction with other treatment strategies. “ http://www.ncbi.nlm.nih.gov/pubmed/25669486

Proapoptotic effect of endocannabinoids in prostate cancer cells.

“Recent evidence shows that derivatives of Cannabis sativa and its analogs may exert a protective effect against different types of oncologic pathologies.”
“Based on these results, we suggest that endocannabinoids may be a beneficial option for the treatment of prostate cancer that has become nonresponsive to common therapies.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358087

Use and medicalization of marihuana in cancer patients.

“Anecdotal reports and some clinical studies suggest that marihuana (Cannabis sativa) is effective in treating a variety of conditions such as glaucoma, migraine, pain, spasticity of multiple sclerosis, anorexia, insomnia, depression, nausea and vomiting. One of the diseases mostly associated to a beneficial effect from marihuana is cancer.”
“This article discusses scientific evidence and information provided by prestigious organizations on the effectiveness and safety of marihuana and its derivatives in cancer patients.” http://www.ncbi.nlm.nih.gov/pubmed/25508539

Cannabinoids increase lung cancer cell lysis by lymphokine-activated killer cells via upregulation of ICAM-1.

“Cannabinoids have been shown to promote the expression of the intercellular adhesion molecule 1 (ICAM-1) on lung cancer cells as part of their anti-invasive and antimetastatic action. Using lung cancer cell lines (A549, H460) and metastatic cells derived from a lung cancer patient, the present study addressed the impact of cannabinoid-induced ICAM-1 on cancer cell adhesion to lymphokine-activated killer (LAK) cells and LAK cell-mediated cytotoxicity. Cannabidiol (CBD), a non-psychoactive cannabinoid, enhanced the susceptibility of cancer cells to adhere to and subsequently be lysed by LAK cells, with both effects being reversed by a neutralizing ICAM-1 antibody.”
“..cannabinoid-induced upregulation of ICAM-1 on lung cancer cells to be responsible for increased cancer cell lysis by LAK cells. These findings provide proof for a novel antitumorigenic mechanism of cannabinoids.”http://www.ncbi.nlm.nih.gov/pubmed/term=CANNABINOIDS+INCREASE+LUNG+CANCER+CELL+LYSIS+BY…

Patterns of Use of Medical Cannabis Among Israeli Cancer Patients: A Single Institution Experience.

“The use of the cannabis plant (Cannabis sativa L.) for the palliative treatment of cancer patients has been legalized in multiple jurisdictions including Israel.”
“Cannabis use is perceived as highly effective by some patients with advanced cancer and its administration can be regulated, even by local authorities. Additional studies are required in order to evaluate the efficacy of cannabis as part of the palliative treatment of cancer patients.” http://www.ncbi.nlm.nih.gov/pubmed/24937161

Down-regulation of cyclooxygenase-2 (COX-2) by cannabidiolic acid in human breast cancer cells.

“Metastases are known to be responsible for approximately 90% of breast cancer-related deaths. Cyclooxygenase-2 (COX-2) is involved not only in inflammatory processes, but also in the metastasis of cancer cells; it is expressed in 40% of human invasive breast cancers. To comprehensively analyze the effects of cannabidiolic acid (CBDA), a selective COX-2 inhibitor found in the fiber-type cannabis plant (Takeda et al., 2008), on COX-2 expression and the genes involved in metastasis, we performed a DNA microarray analysis of human breast cancer MDA-MB-231 cells, which are invasive breast cancer cells that express high levels of COX-2, treated with CBDA for 48 hr at 25 µM. The results obtained revealed that COX-2 and Id-1, a positive regulator of breast cancer metastasis, were down-regulated (0.19-fold and 0.52-fold, respectively), while SHARP1 (or BHLHE41), a suppressor of breast cancer metastasis, was up-regulated (1.72-fold) and CHIP (or STUB1) was unaffected (1.03-fold). These changes were confirmed by real-time RT-PCR analyses. Taken together, the results obtained here demonstrated that i) CBDA had dual inhibitory effects on COX-2 through down-regulation and enzyme inhibition, and ii) CBDA may possess the ability to suppress genes that are positively involved in the metastasis of cancer cells in vitro.” http://www.ncbi.nlm.nih.gov/pubmed/25242400

Δ9-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: Possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells.

“We recently reported that Δ9-tetrahydrocannabinol (Δ9-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2 hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells.”
“Taken together, these results support the concept that the induced levels of PPARα may be involved in the Δ9 THC up-regulation of FA2H in MDA-MB-231 cells.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258431/

Cannabinoids as therapeutic agents in cancer: current status and future implications.

“The pharmacological importance of cannabinoids has been in study for several years. Cannabinoids comprise of (a) the active compounds of the Cannabis sativa plant, (b) endogenous as well as (c) synthetic cannabinoids. Though cannabinoids are clinically used for anti-palliative effects, recent studies open a promising possibility as anti-cancer agents. They have been shown to possess anti-proliferative and anti-angiogenic effects in vitro as well as in vivo in different cancer models. Cannabinoids regulate key cell signaling pathways that are involved in cell survival, invasion, angiogenesis, metastasis, etc. There is more focus on CB1 and CB2, the two cannabinoid receptors which are activated by most of the cannabinoids. In this review article, we will focus on a broad range of cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities.” http://www.ncbi.nlm.nih.gov/pubmed/25115386

Targeting multiple cannabinoid antitumor pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer.

“The psychoactive cannabinoid Δ(9) -tetrahydrocannabinol (THC) and the non-psychoactive cannabinoid cannabidiol (CBD) can both reduce cancer progression, each through distinct anti-tumour pathways. Our goal was to discover a compound that could efficiently target both cannabinoid anti-tumour pathways.”

“CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1.”
“Of all the compounds tested, it was the most potent at inhibiting breast cancer cell proliferation and invasion in culture and metastasis in vivo.”
“O-1663 prolonged survival in advanced stages of breast cancer metastasis. Developing compounds that can simultaneously target multiple cannabinoid anti-tumour pathways efficiently may provide a novel approach for the treatment of patients with metastatic breast cancer.” http://www.ncbi.nlm.nih.gov/pubmed/24910342

WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPARγ down-regulation.

“Cannabinoids have been reported to possess anti-tumorigenic activity in cancer models…”
“Here, we show that the synthetic cannabinoid WIN55,212-2 (WIN)-induced apoptosis in colon cancer cell lines is accompanied by endoplasmic reticulum stress induction.” http://www.ncbi.nlm.nih.gov/pubmed/24696378

Antineoplastic Effect of WIN 55,212-2, a Cannabinoid Agonist, in a Murine Xenograft Model of Gastric Cancer.

“We have previously reported the antineoplastic effects of a cannabinoid agonist in gastric cancer cells.”
“A cannabinoid agonist, WIN 55,212-2 (7 mg/kg body weight) or vehicle was injected around the tumor subcutaneously every 24 h for 14 days. Tumors were explanted for analysis.”
“Tumor volume decreased by 30% in the WIN 55,212-2-treated group compared to the group treated with vehicle (p < 0.05). Apoptotic cells were found more commonly in the WIN 55,212-2 treatment group than in the control on immunohistochemistry. Compared to the control, WIN 55,212-2 treatment significantly increased caspase-3 cleavage and decreased MMP-2, MMP-7 and MMP-9 protein levels significantly (all p < 0.05).”
“WIN 55,212-2 has antineoplastic effect on the gastric cancers in in vivo model.” http://www.ncbi.nlm.nih.gov/pubmed/24335109

Combined antiproliferative effects of the aminoalkylindole WIN55,212-2 and radiation in breast cancer cells.

“The antiproliferative effects produced by combination of WIN2 and radiation were more effective than either agent alone. “
“.., the observation that WIN2 interfered with growth stimulation by sphingosine-1-phosphate (S1P) implicates the potential involvement of S1P/ceramide signaling pathways. In addition to demonstrating that aminoalkylindole compounds could potentially augment the effectiveness of radiation treatment in breast cancer, the present study suggests that THC and nabilone are unlikely to interfere with the effectiveness of radiation therapy, which is of particular relevance to patients using cannabinoid-based drugs to ameliorate the toxicity of cancer therapies.” http://www.ncbi.nlm.nih.gov/pubmed/24259678

Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1.

“Cannabinoids, in addition to having palliative benefits in cancer therapy, have been associated with anticarcinogenic effects.”
“Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.”
Free full text: http://jnci.oxfordjournals.org/content/100/1/59.long

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1.

“Here we evaluated the impact of cannabidiol, a plant-derived non-psychoactive cannabinoid, on cancer cell invasion.”
“Altogether, these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.” http://www.ncbi.nlm.nih.gov/pubmed/19914218

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1.

“Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1).”
“Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.” http://www.ncbi.nlm.nih.gov/pubmed/22198381

Critical appraisal of the potential use of cannabinoids in cancer management.

“Cannabinoids have been attracting a great deal of interest as potential anticancer agents. Originally derived from the plant Cannabis sativa, there are now a number of endo-, phyto- and synthetic cannabinoids available. This review summarizes the key literature to date around the actions, antitumor activity, and mechanisms of action for this broad range of compounds. Cannabinoids are largely defined by an ability to activate the cannabinoid receptors – CB1 or CB2. The action of the cannabinoids is very dependent on the exact ligand tested, the dose, and the duration of exposure. Some cannabinoids, synthetic or plant-derived, show potential as therapeutic agents, and evidence across a range of cancers and evidence in vitro and in vivo is starting to be accumulated. Studies have now been conducted in a wide range of cell lines, including glioma, breast, prostate, endothelial, liver, and lung. This work is complemented by an increasing body of evidence from in vivo models.” Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770515/

The Medical Necessity for Medicinal Cannabis: Prospective, Observational Study Evaluating the Treatment in Cancer Patients on Supportive or Palliative Care

“Cancer patients using cannabis report better influence from the plant extract than from synthetic products.”
“All cancer or anticancer treatment-related symptoms showed significant improvement ( ).”
“The positive effects of cannabis on various cancer-related symptoms are tempered by reliance on self-reporting for many of the variables. Although studies with a control group are missing, the improvement in symptoms should push the use of cannabis in palliative treatment of oncology patients.” Full text: http://www.hindawi.com/journals/ecam/2013/510392/

Cannabinoid receptor agonist as an alternative drug in 5-fluorouracil-resistant gastric cancer cells.

“In this study, we investigated the effects of a cannabinoid agonist, WIN-55,212-2, on 5-fluorouracil (5-FU)-resistant human gastric cancer cells, to examine whether the cannabinoid agonist may be an alternative therapy.”
“These results indicate that a cannabinoid agonist may, indeed, be an alternative chemotherapeutic agent for 5-FU-resistant gastric cancer.” http://www.ncbi.nlm.nih.gov/pubmed/23749906

The X-Change Corporation Sees More Evidence of Treatment Benefits of Cannabinoids For Life Threatening Cancer Conditions

“Anecdotal results of self-treated patients have evidenced dramatic therapeutic results from cannabinoid-based treatments. Cannabis Science, Inc. and X-Change Corp are collaborating to document the clinical efficacy of such treatments. “ http://www.prnewswire.com/news-releases/the-x-change-corporation-sees-more-evidence-of-treatment-benefits-of-cannabinoids-for-life-threatening-cancer-conditions-218723051.html

 

“Cannabidiol, a safe and non-psychotropic ingredient of Cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentially beneficial for colon carcinogenesis.” “Cannabidiol-reduced ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation in a CB(1)-, TRPV1- and PPARγ-antagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effect in vivo and reduces cell proliferation through multiple mechanisms.” http://www.ncbi.nlm.nih.gov/pubmed/22231745

Cannabidiol as potential anticancer drug.

“Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Δ9-tetrahydrocannabinol (Δ9-THC), synthetic agonists, endocannabinoids and endocannabinoid transport or degradation inhibitors.” “The present review will focus on the efficacy of CBD in the modulation of different steps of tumourigenesis in several types of cancer and highlights the importance of exploring CBD/CBD analogues as alternative therapeutic agents.” “Cannabinoids are currently used in cancer patients to palliate wasting, emesis and pain that often accompany cancer. A significant advancement in cannabinoid use in cancer treatment came from the discovery of a potential utility of these compounds for targeting and killing cancer cells. In 1975 Munson et al. [17] demonstrated that the administration of Δ9-THC, Δ8-THC and cannabinol inhibited the growth of Lewis lung adenocarcinoma cells in vitro as well as in vivo after oral administration in mice.” “Moreover, other antitumourigenic mechanisms of cannabinoids are currently emerging, showing their ability to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization [27].” “Besides its beneficial effects in the treatment of pain and spasticity and other CNS pathologies, several reports demonstrated that CBD possesses antiproliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion.” CBD and breast cancer “In 2006 Ligresti et al. [30] demonstrated for the first time that CBD potently and selectively inhibited the growth of different breast tumour cell lines (MCF7, MDA-MB-231), with an IC50 of about 6 µm, and exhibited significantly lower potency in non-cancer cells. CBD and CBD-rich extracts (containing approximately 70% CBD together with lesser amounts of other cannabinoids) also inhibited the growth of xenografts, obtained by s.c. injection into athymic mice of human MDA-MB-231 cells, and reduced infiltration of lung metastases derived from intrapaw injection of breast carcinoma cells. “ “As a whole this work highlights the presence of a complex balance between autophagy and mitochondria-mediated apoptosis in CBD-induced breast cancer cell death and strengthens the idea that CBD can be considered as an alternative agent for breast cancer therapy” CBD and glioma “CBD also possesses anti-tumoural properties in gliomas, tumours of glial origin characterized by a high morphological and genetic heterogeneity and considered one of the most devastating neoplasms, showing high proliferative rate, aggressive invasiveness and insensitivity to radio- and chemotherapy” “Besides cell growth, CBD reduced glioma cell migration [43] and invasiveness in a Boyden chamber test [39], at concentrations lower than those required to inhibit cell proliferation. “ “CBD seems to counteract glioma cell proliferation and invasion through multiple mechanisms, as summarized in …” CBD and leukaemia/lymphoma “Gallily et al. [44] provided first evidence of a possible exploitation of CBD in the treatment of lymphoblastic diseases. They demonstrated that CBD treatment induced apoptosis, through caspase-3 activation in human acute myeloid leukaemia HL-60 cell line, whereas it had no effect on human monocytes from normal individuals.” “Together, the results suggest that CBD, acting through CB2 receptors and ROS production, may represent a novel and highly selective treatment for leukaemia. Moreover, previous evidence indicated that human leukaemias and lymphomas expressed significantly higher levels of CB2 receptors compared with other tumour cell lines, suggesting that tumours of immune origin may be highly sensitive to the CB2-mediated effects of CBD [46].” CBD and lung cancer “Recently, Ramer et al. [51–53] investigated the effect of CBD on the invasive properties of A549 cells, a line of human lung carcinoma cells expressing both CB1 and CB2, as well as TRPV1 receptors. Using Matrigel invasion assays, they found a CBD-driven impaired invasion of A549 cells that was reversed by CB1 and CB2 receptors as well as TRPV1 antagonists.” “Additionally,in vivo studies in thymic aplastic nude mice revealed a significant inhibition of A549 lung metastases following CBD treatment [51] and a significant downregulation of PAI-1 protein was demonstrated in A549 xenografts of CBD-treated rats [52].” “It is worth noting that CBD decreased invasiveness in a range of therapeutically relevant concentrations (0.01 to 0.05 µm), since the peak plasma concentrations of CBD in healthy volunteers following administration of Sativex™ (1:1 ratio of Δ9-THC and CBD) was reported to be between 0.01 µm to 0.05 µm[54].” “Together, these findings provide a novel mechanism underlying the anti-invasive action of CBD on human lung cancer cells and imply its use as a therapeutic option for the treatment of highly invasive cancers.” CBD and endocrine tumours “Thyroid cancer is the most common endocrine malignancy and Ligresti et al. [30] demonstrated that CBD exerted anti-proliferative effects on rat thyroid KiMol cells, transformed with the v-K-ras oncogene. This effect of CBD was associated with a cell cycle block at the G1/S phase transition, as well as the induction of apoptosis.” “Later on, Lee et al. [55] demonstrated that CBD markedly induced apoptosis in both murine thymocytes and EL-4 thymoma cells, with CBD-mediated apoptosis occurring earlier in EL-4 cells than in thymocytes.” “The observation that CBD induced oxidative stress in thymocytes, EL-4 cells and splenocytes [56] substantiates the notion that, unlike monocytes, T cells both primary and immortalized, are all sensitive and respond similarly to CBD, with a central role of ROS generation.” CBD and colon cancer “Colon cancer is a major cause of morbidity and mortality in Western countries. A recent paper from Izzo’s group [57] demonstrated the chemopreventive effect of CBD in a preclinical animal model of colon cancer based on azoxymethane (AOM) administration in mice.” “CBD was effective in reducting ACF, polyps and tumours and counteracted AOM-induced phospho-Akt and caspase-3 changes. In vitro studies, supported the beneficial effect of CBD. Indeed, in colorectal carcinoma cell lines, CBD protected DNA from oxidative damage, increased endocannabinoid concentrations and reduced cell proliferation in a CB1-, TRPV1- and PPARγ-antagonist sensitive manner.” “In the light of its safety records, these results suggest that CBD might be worthy of clinical consideration in colon cancer prevention.” CBD and angiogenesis “Collectively, cannabinoids have been demonstrated to act as anti-angiogenic factors by disposing tumour cells to decrease the production of pro-angiogenic factors and/or by direct modulation of endothelial cells [27].” “Collectively, these preliminary data demonstrate that, besides its well known pro-apoptotic anti-proliferative and anti-invasive actions, CBD may also exert anti-angiogenic effects, thus further strengthening its potential application in cancer therapy.” “Collectively, the non-psychoactive plant-derived cannabinoid CBD exhibits pro-apoptotic and anti-proliferative actions in different types of tumours and may also exert anti-migratory, anti-invasive, anti-metastatic and perhaps anti-angiogenic properties. On the basis of these results, evidence is emerging to suggest that CBD is a potent inhibitor of both cancer growth and spread.” “Interestingly, the anticancer effect of this compound seems to be selective for cancer cells, at least in vitro, since it does not affect normal cell lines.” “In the light of its safety record and considering that CBD is already currently used in patients with multiple sclerosis, the findings here summarized suggest that CBD might be worthy of clinical consideration for cancer therapy.” Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579246/

 

The atypical cannabinoid O-1602 shows antitumorigenic effects in colon cancer cells and reduces tumor growth in a colitis-associated colon cancer model

“Cannabinoids and the endocannabinoid system play an important role the protection against inflammation and cancer.” “O-1602 exerts antitumorigenic effects by targeting colon cancer cells as well as proinflammatory pathways known to promote colitis-associated tumorigenesis, thus providing a novel insight into antitumorigenic mechanisms of atypical cannabinoids. As O-1602 is free of central sedation, it could be an interesting compound for the treatment of colon and possibly other cancers.” Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506320/

Autophagy in pancreatic cancer pathogenesis and treatment

“Pancreatic cancer is the fourth most common cancer to cause death due to advanced stage at diagnosis and poor response to current treatment.” “..autophagy plays multiple roles in the regulation of pancreatic cancer pathogenesis and treatment, although the exact mechanisms remain unknown.” “Indeed, cannabinoids are also an apoptotic inducer by activation of the endoplasmic reticulum stress pathway in pancreatic cancer cells [120].” Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410583/

Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis

“Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Therefore, effective, targeted, and non-toxic therapies are urgently required.” “We previously reported that cannabidiol (CBD), a cannabinoid with a low toxicity pro-file, down-regulated Id-1 gene expression in aggressive human breast cancer cells in culture.” “We show that CBD inhibits human breast cancer cell proliferation and invasion through differential modulation of the extracellular signal-regulated kinase (ERK) and reactive oxygen species (ROS) pathways, and that both pathways lead to down-regulation of Id-1 expression. Moreover, we demonstrate that CBD up-regulates the pro-differentiation factor, Id-2. Using immune competent mice, we then show that treatment with CBD significantly reduces primary tumor mass as well as the size and number of lung metastatic foci in two models of metastasis. Our data demonstrate the efficacy of CBD in pre-clinical models of breast cancer. The results have the potential to lead to the development of novel non-toxic compounds for the treatment of breast cancer metastasis, and the information gained from these experiments broaden our knowledge of both Id-1 and cannabinoid biology as it pertains to cancer progression.” http://www.ncbi.nlm.nih.gov/pubmed/20859676

High Tumour Cannabinoid CB1 Receptor Immunoreactivity Negatively Impacts Disease-Specific Survival in Stage II Microsatellite Stable Colorectal Cancer

“There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB1 receptor immunoreactive intensity (CB1IR intensity) is associated with disease severity and outcome.” “The level of CB1 receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB1IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.” http://www.ncbi.nlm.nih.gov/pubmed/21901119

Crosstalk between Chemokine Receptor CXCR4 and Cannabinoid Receptor CB2 in Modulating Breast Cancer Growth and Invasion

“Cannabinoids bind to cannabinoid receptors CB1 and CB2 and have been reported to possess anti-tumorigenic activity in various cancers.” “In this study, we report that a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB2 may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12. This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis.” “Furthermore, these studies indicate that CB2 receptors could be used for developing innovative therapeutic strategies against breast cancer.” http://www.ncbi.nlm.nih.gov/pubmed/21915267

The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications

“Prostate cancer is a global public health problem, and it is the most common cancer in American men and the second cause for cancer-related death.” “Prostate cancer cells possess increased expression of both cannabinoid 1 and 2 receptors, and stimulation of these results in decrease in cell viability, increased apoptosis, and decreased androgen receptor expression and prostate-specific antigen excretion. It would be of interest to conduct clinical studies utilizing cannabinoids for patients with metastatic prostate cancer, taking advantage not only of its beneficial effects on prostate cancer but also of their analgesic properties for bone metastatic cancer pain.” “Cannabinoid CB1 receptors are found mainly in the central nervous system and, in less abundance, in certain peripheral tissues.[36] At the peripheral level, they are localized in the adrenal gland, adipose tissue, heart, liver, lung, prostate, uterus, ovary, testis, bone marrow, thymus, tonsils, and presynaptic nerve terminals.” “The distribution of cannabinoid receptors provides an anatomical explanation for the analgesic effects of the cannabinoids.” “Clinical trials have shown that nonselective cannabinoid receptor agonists are relatively safe and therapeutically efficacious, however, inducing also psychotropic side effects.[59] Cannabinoid efficacy has also been studied clinically in cancer pain. Initial studies quantified the modest efficacy of oral 20 mg D9-THC equivalent to 120 mg codeine with some sedation, dizziness, and confusion.[54,60,61] Recently in an observational study of patients with advanced cancer pain, nabilone reduced pain scores, total opioid requirements, and nausea. Nabilone did not significantly increase adverse effects compared with the control group, and this fact could be attributed to the concurrent decrease in opioid dose.[62]” “Cannabinoids possess attributes that have impact in both cancer pain and prostate cancer pathophysiology. These compounds harbor analgesic properties that aid bone cancer pain, reduce opioid consumption, side effects, and dependence, as well as exhibiting anti-androgenic effects on experimental prostate cancer cells.” “In 2005, Sarfaraz and colleagues[30] showed increased expression of both CB1 and CB2 receptors in cultured prostate cancer cells when compared with normal prostate cells, treatment of prostate cancer cells with cannabinoid CB1/CB2 agonist WIN-55,212-2 results in a dose and time dependent decrease in cell viability ,and increased apoptosis along with decrease in androgen receptor protein expression, PSA expression, and secreted PSA, suggesting that cannabinoids should be considered as agents for the management of prostate cancer. If the hypothesis is supported by in vivo experiments. It is our conclusion that it would be of interest to conduct clinical trials involving medicinal cannabis or other cannabinoid agonists, comparing clinical markers such as PSA with controls, especially in men with bone metastatic prostate cancer, whom would not only benefit from the possible anti-androgenic effects of cannabinoids but also from analgesia of bone pain, improving quality of life, while reducing narcotic consumption and preventing opioid dependence.” http://www.ncbi.nlm.nih.gov/pubmed/22557710

A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss

“Cannabinoid CB2 agonists have been shown to alleviate behavioral signs of inflammatory and neuropathic pain in animal models” “Metastatic bone cancer causes severe pain in patients and is treated with analgesics such as opiates. Recent reports suggest that sustained opiates can produce paradoxical hyperalgesic actions and enhance bone destruction in a murine model of bone cancer. In contrast, CB2 selective agonists have been shown to reduce bone loss associated with a model of osteoporosis. Here we tested whether a CB2 agonist administered over a 7 day period inhibits bone cancer-induced pain as well as attenuates cancer-induced bone degradation.” “In addition, CB2 agonist do not result in the many unwanted side effects of current analgesic therapies due to its lack of direct activity on neuronal pathways within the rewarding and respiratory pathways of the CNS suggesting that CB2 agonists may be an ideal treatment for bone cancer pain.” http://www.ncbi.nlm.nih.gov/pubmed/20176037

Induction of Apoptosis by Cannabinoids in Prostate and Colon Cancer Cells Is Phosphatase Dependent

(Apoptosis is programmed cell death, cell suicide. Cannabinoids come from cannabis. This science says: “We hypothesized that the anticancer activity of cannabinoids was linked to induction of phosphatases.) “We hypothesized that the anticancer activity of cannabinoids was linked to induction of phosphatases.” “CBD and WIN inhibited LNCaP and SW480 cell growth and induced mRNA expression of several phosphatases, and the phosphatase inhibitor sodium orthovanadate significantly inhibited cannabinoid-induced PARP cleavage in both cell lines, whereas only CBD-induced apoptosis was CB1 and CB2 receptor-dependent.” “Cannabinoid receptor agonists induce phosphatases and phosphatase-dependent apoptosis in cancer cell lines; however, the role of the CB receptor in mediating this response is ligand-dependent.” “The results obtained using the phosphatase inhibitor SOV demonstrate that induction of apoptosis by WIN and CBD was significantly blocked by the phosphatase inhibitor SOV, and this represents a novel proapoptotic pathway induced by cannabinoids. Current studies are focused on identification of specific proapoptotic phosphatases and their mechanisms of induction or activation by cannabinoids.” http://www.ncbi.nlm.nih.gov/pubmed/22110202

Cannabinoids Attenuate Cancer Pain and Proliferation in a Mouse Model

“We investigated the effects of cannabinoid receptor agonists on (1) oral cancer cell viability in vitro and (2) oral cancer pain and tumor growth in a mouse cancer model. We utilized immunohistochemistry and Western blot to show that human oral cancer cells express CBr1 and CBr2. When treated with WIN55,212-2 (non-selective), ACEA (CBr1-selective) or AM1241 (CBr2-selective) agonists in vitro, oral cancer cell proliferation was significantly attenuated in a dose-dependent manner. In vivo, systemic administration (0.013M) of WIN55,212-2, ACEA, or AM1241 significantly attenuated cancer-induced mechanical allodynia. Tumor growth was also significantly attenuated with systemic AM1241 administration. Our findings suggest a direct role for cannabinoid mechanisms in oral cancer pain and proliferation. The systemic administration of cannabinoid receptor agonists may have important therapeutic implications wherein cannabinoid receptor agonists may reduce morbidity and mortality of oral cancer.” http://www.ncbi.nlm.nih.gov/pubmed/21094209

The endocannabinoid system and cancer: therapeutic implication

“The endocannabinoid system is implicated in a variety of physiological and pathological conditions (inflammation, immunomodulation, analgesia, cancer and others). The main active ingredient of cannabis, Δ(9) -tetrahydrocannabinol (Δ(9) -THC), produces its effects through activation of CB(1) and CB(2) receptors. CB(1) receptors are expressed at high levels in the central nervous system (CNS), whereas CB(2) receptors are concentrated predominantly, although not exclusively, in cells of the immune system.” “Here we review the relationship between the endocannabinoid system and anti-tumour actions (inhibition of cell proliferation and migration, induction of apoptosis, reduction of tumour growth) of the cannabinoids in different types of cancer. This review will focus on examining how activation of the endocannabinoid system impacts breast, prostate and bone cancers in both in vitro and in vivo systems. The therapeutic potential of cannabinoids for cancer, as identified in clinical trials, is also discussed. Identification of safe and effective treatments to manage and improve cancer therapy is critical to improve quality of life and reduce unnecessary suffering in cancer patients. In this regard, cannabis-like compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients. Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted.” http://www.ncbi.nlm.nih.gov/pubmed/21410463

Towards the use of non-psychoactive cannabinoids for prostate cancer.

“The palliative effects of Cannabis sativa (marijuana), and its putative main active ingredient, Δ(9) -tetrahydrocannabinol (THC), which include appetite stimulation, attenuation of nausea and emesis associated with chemo- or radiotherapy, pain relief, mood elevation, and relief from insomnia in cancer patients, are well-known” “In this issue of the British Journal of Pharmacology, De Petrocellis and colleagues present comprehensive evidence that plant-derived cannabinoids, especially cannabidiol, are potent inhibitors of prostate carcinoma viability in vitro. They also showed that the extract was active in vivo, either alone or when administered with drugs commonly used to treat prostate cancer (the anti-mitotic chemotherapeutic drug docetaxel (Taxotere) or the anti-androgen bicalutamide (Casodex)) and explored the potential mechanisms behind these antineoplastic effects.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570005/

Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists.

“The systemic administration of a CB(2) agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB(2) -mediated effects in vivo were reversed by concurrent treatment with a CB(2) antagonist/inverse agonist but not with a CB(1) antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB(2) agonists as a novel treatment for breast cancer-induced bone pain, in which disease modifications include a reduction in bone loss, suppression of cancer growth, attenuation of severe bone pain, and increased survival without the major side effects of current therapeutic options.” http://www.ncbi.nlm.nih.gov/pubmed/22903605

Expression of the cannabinoid type I receptor and prognosis following surgery in colorectal cancer.

“The cannabinoid system has been considered to be a potential target of colorectal carcinoma therapy.” “The high immunoreactivity of the cannabinoid type 1 receptor is a significant prognostic factor following surgery in stage IV CRC.” “Antineoplastic effects are mediated by the activation of cannabinoid type I (CB1), type 2 (CB2) or a non-cannabinoid receptor-mediated mechanism (6). Among the receptors, the mechanism of tumor cell apoptosis has been rigorously investi gated by several research groups who have studied the CB1 receptor (2–5).” “The evidence mentioned thus far suggests that the endogenous cannabinoid system is able to regulate cancer progression and affect disease progression and outcomes.” http://www.ncbi.nlm.nih.gov/pubmed/23426698

COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells.

“This study investigates the role of COX-2 and PPAR-γ in cannabidiol’s proapoptotic and tumor-regressive action.” “In lung cancer cell lines (A549, H460) and primary cells from a patient with lung cancer, cannabidiol elicited decreased viability associated with apoptosis. Apoptotic cell death by cannabidiol was suppressed by NS-398 (COX-2 inhibitor), GW9662 (PPAR-γ antagonist), and siRNA targeting COX-2 and PPAR-γ. Cannabidiol-induced apoptosis was paralleled by upregulation of COX-2 and PPAR-γ mRNA and protein expression with a maximum induction of COX-2 mRNA after 8 hours and continuous increases of PPAR-γ mRNA when compared with vehicle. In response to cannabidiol, tumor cell lines exhibited increased levels of COX-2-dependent prostaglandins (PG) among which PGD(2) and 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) caused a translocation of PPAR-γ to the nucleus and induced a PPAR-γ-dependent apoptotic cell death.” “Together, our data show a novel proapoptotic mechanism of cannabidiol involving initial upregulation of COX-2 and PPAR-γ and a subsequent nuclear translocation of PPAR-γ by COX-2-dependent PGs.” http://www.ncbi.nlm.nih.gov/pubmed/23220503

Preparation and characterization of Δ9-tetrahydrocannabinol-loaded biodegradable polymeric microparticles and their antitumoral efficacy on cancer cell lines.

“Cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer, AIDS and multiple sclerosis), analgesics, and in the treatment of multiple sclerosis and cancer, among other conditions.” “As THC has shown therapeutic potential as anticancer drug, the efficacy of the microspheres was tested on different cancer cell lines. Interestingly, the microspheres were able to inhibit cancer cell proliferation during the nine-day study period. All the above results suggest that the use of biodegradable microspheres would be a suitable alternative delivery system for THC administration.” http://www.ncbi.nlm.nih.gov/pubmed/23773072

Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells.

“The anti-tumoral effects of cannabinoids have been described in different tumor systems, including pancreatic adenocarcinoma,..” “Altogether, these alterations of pancreatic cancer cell metabolism mediated by cannabinoids result in a strong induction of autophagy and in the inhibition of cell growth.” “In summary, our results demonstrated for the first time that cannabinoid-dependent autophagy induction in pancreatic adenocarcinoma cells is strictly related to the inhibition of the energetic metabolism, which, in turn, is dependent on the early production of ROS induced by the compounds. In Figure 7, we propose a model of the mechanism of autophagy induction by the cannabinoids ACPA and GW in pancreatic adenocarcinoma cells that is based on the results presented in this paper and on literature data.” http://www.ncbi.nlm.nih.gov/pubmed/23764845

Association between Cannabinoid CB1 Receptor Expression and Akt Signalling in Prostate Cancer

“In prostate cancer, tumour expression of cannabinoid CB₁ receptors is associated with a poor prognosis. One explanation for this association comes from experiments with transfected astrocytoma cells, where a high CB receptor expression recruits the Akt signalling survival pathway. In the present study, we have investigated the association between CB₁ receptor expression and the Akt pathway in a well-characterised prostate cancer tissue microarray.” “The present study provides data that is consistent with the hypothesis that at a high CB₁ receptor expression, the Akt signalling pathway becomes operative.” http://www.ncbi.nlm.nih.gov/pubmed/23755281

The endocannabinoid signaling system in cancer.

“Changes in lipid metabolism are intimately related to cancer. Several classes of bioactive lipids play roles in the regulation of signaling pathways involved in neoplastic transformation and tumor growth and progression. The endocannabinoid system, comprising lipid-derived endocannabinoids, their G-protein-coupled receptors (GPCRs), and the enzymes for their metabolism, is emerging as a promising therapeutic target in cancer.” “This report highlights the main signaling pathways for the antitumor effects of the endocannabinoid system in cancer and its basic role in cancer pathogenesis, and discusses the alternative view of cannabinoid receptors as tumor promoters. We focus on new players in the antitumor action of the endocannabinoid system and on emerging crosstalk among cannabinoid receptors and other membrane or nuclear receptors involved in cancer. We also discuss the enzyme MAGL, a key player in endocannabinoid metabolism that was recently recognized as a marker of tumor lipogenic phenotype.” http://www.ncbi.nlm.nih.gov/pubmed/23602129

Cannabinoids may be therapeutic in breast cancer

“Cannabinoids are a group of compounds synthesized exclusively by the Cannabis sativa plant, commonly known as marijuana. In 1990, the first cannabinoid-specific membrane (CB1) was characterized and cloned (Matsuda, Lolait, Brownstein, Young, & Bonner, 1990), which catapulted biomedical research on these unique compounds. Cannabinoids refer to both marijuana-derived compounds with the active ingredient of 9-tetrahydrocannabinol (THC) and also the synthetic molecules that activate the same primary targets as THC. Therapeutic properties of marijuana have been well established.. “The anticachexia properties of cannabinoids are found in tetrahydrocannabinol (oral capsules of synthetically generated THC) and are used to manage weight loss, wasting syndrome, and nausea and vomiting associated with cancer treatment.” http://www.ncbi.nlm.nih.gov/pubmed/23448745

Receptor-dependent and receptor-independent endocannabinoid signaling: a therapeutic target for regulation of cancer growth.

“Here, we briefly review recent works which suggest that (a) CB1/CB2 receptors are possible drug targets for breast and prostate cancer and (b) cannabinoid receptor independent pathways which compose or interact with the endocannabinoid system may also serve as anti-tumor drug targets.” “Recent works have revealed several important interactions between the endocannabinoid system and cancer. Moreover, it is now well established that synthetic small molecule cannabinoid receptor agonist acting on either CB1R or CB2R or both exerts anti-cancer effects on a variety of tumor cells. Recent results from many laboratories reported that the expression of CB1R and CB2R in prostate cancer, breast cancer, and many other cancer cells is higher than that in corresponding non-malignant tissues. The mechanisms by which cannabinoids acting on CB1R or CB2R exert their effects on cancer cells are quite diverse and complex. Further, several studies demonstrated that some of the anti-proliferative and apoptotic effects of cannabinoids are mediated by receptor-independent mechanisms. In this minireview we provide an overview of the major findings on the effects of endogenous and/or synthetic cannabinoids on breast and prostate cancers. We also provide insight into receptor independent mechanisms of the anti-cancer effects of cannabinoids under in vitro and in vivo conditions.” “The identification of effective treatments to manage and improve cancer therapy is of paramount importance. Selective inhibition of cannabinoid receptors offers potential for the treatment of many cancers including prostate and breast. In addition, several published works show that other components of the endogenous cannabinoid system may serve as drug targets since cannabinoids display anticancer effects independent of cannabinoid receptors.” http://www.ncbi.nlm.nih.gov/pubmed/23069587

Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy.

“Cannabidiol (CBD), a major nonpsychoactive constituent of cannabis, is considered an antineoplastic agent on the basis of its in vitro and in vivo activity against tumor cells. “ “Our study revealed an intricate interplay between apoptosis and autophagy in CBD-treated breast cancer cells and highlighted the value of continued investigation into the potential use of CBD as an antineoplastic agent.” http://www.ncbi.nlm.nih.gov/pubmed/21566064

Cannabinoids inhibit cellular respiration of human oral cancer cells.

“The primary cannabinoids, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) are known to disturb the mitochondrial function and possess antitumor activities.” “These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.” http://www.ncbi.nlm.nih.gov/pubmed/20516734
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Cannabis extract treatment for terminal acute lymphoblastic leukemia with a Philadelphia chromosome mutation.

“..Cannabinoid resin extract is used as an effective treatment for ALL with a positive Philadelphia chromosome mutation and indications of dose-dependent disease control. The clinical observation in this study revealed a rapid dose-dependent correlation.” “It is tempting to speculate that, with integration of this care in a setting of full medical and laboratory support, a better outcome may indeed be achieved in the future.” http://www.ncbi.nlm.nih.gov/pubmed/24474921  

Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol.

“Colon cancer is a major public health problem. Cannabis-based medicines are useful adjunctive treatments in cancer patients.” “CBD BDS and CBD reduced cell proliferation in tumoral, but not in healthy, cells. “ “CBD BDS attenuates colon carcinogenesis and inhibits colorectal cancer cell proliferation via CB1 and CB2 receptor activation. The results may have some clinical relevance for the use of Cannabis-based medicines in cancer patients.” BDS = botanical drug substance http://www.ncbi.nlm.nih.gov/pubmed/24373545 THC (cannabis) Helps Cure Cancer Says Harvard Study “Researchers at Harvard tested the chemical THC in both lab and mouse studies. They say this is the first set of experiments to show that the compound, THC actually activates naturally produced receptors to fight off lung cancer. The researchers suggest that THC or other designer agents that activate these receptors might be used in a targeted fashion to treat lung cancer.” “*HERE IS THE INTERESTING PART* The only clinical trial testing THC as a treatment against cancer growth was a recently completed British pilot study. For three weeks, researchers injected standard doses of THC into mice that had been implanted with human lung cancer cells, and found that tumors were reduced in size and weight by about 50 percent in treated animals compared to a control group. There was also about a 60 percent reduction in cancer lesions on the lungs in these mice as well as a significant reduction in protein markers associated with cancer progression.” https://www.ncbi.nlm.nih.gov/pubmed/24373545

THC (marijuana) Helps Cure Cancer Says Harvard Study

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Marijuana Chemical May Fight Brain Cancer

Active Component In Marijuana Targets Aggressive Brain Cancer Cells, Study Says

“The active chemical in marijuana promotes the death of brain cancer cells by essentially helping them feed upon themselves, researchers in Spain report.” “Guillermo Velasco and colleagues at Complutense University in Spain have found that the active ingredient in marijuana, THC, causes brain cancer cells to undergo a process called autophagy. Autophagy is the breakdown of a cell that occurs when the cell essentially self-digests. The team discovered that cannabinoids such as THC had anticancer effects in mice with human brain cancer cells and people with brain tumors. When mice with the human brain cancer cells received the THC, the tumor growth shrank. Two patients enrolled in a clinical trial received THC directly to the brain as an experimental treatment for recurrent glioblastoma multiforme, a highly aggressive brain tumor. Biopsies taken before and after treatment helped track their progress. After receiving the THC, there was evidence of increased autophagy activity.” “The patients did not have any toxic effects from the treatment. Previous studies of THC for the treatment of cancer have also found the therapy to be well tolerated, according to background information in journal article. Study authors say their findings could lead to new strategies for preventing tumor growth.” http://www.webmd.com/cancer/brain-cancer/news/20090401/marijuana-chemical-may-fight-brain-cancer

CANNABIS SCIENCE EXTRACTS KILL CANCER CELLS IN CANCER PATIENTS BEING TREATED THROUGH ITS LICENSED DISTRIBUTOR ROCKBROOK

“a patient with basal cell carcinoma used a topical formulation to dramatically and rapidly eliminate her obvious skin cancer. Meanwhile, patients with internal tumors used oral formulations for their treatment. We currently await more complete clinical evaluations of the patients’ own reports of dramatic health improvements coincident with tumor shrinkage and disappearance.” http://www.cannabisscience.com/index.php/2011/496-cannabis-science-extracts-kill-cancer-cells-in-cancer-patients-being-treated-through-its-licensed-distributor-rockbrook http://www.businesswire.com/news/home/20110222007195/en/Cannabis-Science-Extracts-Kill-Cancer-Cells-Cancer~~~#.VTCYL1w4zA4

THC at high doses locally, inhibits cholangiocarcinoma cancer…

 

The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration. at high concentration.

“The anticancer effect of Delta (9)-tetrahydrocannabinol (THC), the principal active component of cannabinoids has been demonstrated in various kinds of cancers. “ “THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis. THC also decreased actin polymerization and reduced tumor cell survival in anoikis assay.” “Consequently, THC is potentially used to retard cholangiocarcinoma cell growth and metastasis.” http://www.ncbi.nlm.nih.gov/pubmed/19916793

Marijuana Cuts Lung Cancer Tumor Growth In Half, Study Shows

“The active ingredient in marijuana cuts tumor growth in common lung cancer in half and significantly reduces the ability of the cancer to spread, say researchers at Harvard University who tested the chemical in both lab and mouse studies” “The researchers suggest that THC or other designer agents that activate these receptors might be used in a targeted fashion to treat lung cancer.” “”The beauty of this study is that we are showing that a substance of abuse, if used prudently, may offer a new road to therapy against lung cancer,” said Anju Preet, Ph.D., a researcher in the Division of Experimental Medicine.” http://www.sciencedaily.com/releases/2007/04/070417193338.htm

THC inhibits Lung Cancer Growth

Δ9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo

“Δ⁹-Tetrahydrocannabinol (THC) is the primary cannabinoid of marijuana and has been shown to either potentiate or inhibit tumor growth, depending on the type of cancer and its pathogenesis.”

“Tumor samples from THC-treated animals revealed antiproliferative and antiangiogenic effects of THC. Our study suggests that cannabinoids like THC should be explored as novel therapeutic molecules in controlling the growth and metastasis of certain lung cancers.” http://www.nature.com/onc/journal/v27/n3/abs/1210641a.html

 

Medical marijuana news. Cannabidiol stops the spread of breast cancer.

Cannabidiol researchers discover the switch to turn off aggressive breast cancer gene “We discovered that cannabidiol (CBD), a non-psychotropic compound from the plant Cannabis sativa, can inhibit the processes that allow breast cancer cells to grow and spread (metastasis).” “..CBD is already being tested in the clinic for indication other then cancer and has an established safety profile.” http://www.examiner.com/article/medical-marijuana-news-cannabidiol-stops-the-spread-of-breast-cancer

Raymond Cushing is a journalist, musician and filmmaker. This article was named by Project Censored as a “Top Censored Story of 2000.”
The term medical marijuana took on dramatic new meaning in February, 2000 when researchers in Madrid announced they had destroyed incurable brain tumors in rats by injecting them with THC, the active ingredient in cannabis. The Madrid study marks only the second time that THC has been administered to tumor-bearing animals; the first was a Virginia investigation 26 years ago. In both studies, the THC shrank or destroyed tumors in a majority of the test subjects. Most Americans don’t know anything about the Madrid discovery. Virtually no major U.S. newspapers carried the story, which ran only once on the AP and UPI news wires, on Feb. 29, 2000. The ominous part is that this isn’t the first time scientists have discovered that THC shrinks tumors. In 1974 researchers at the Medical College of Virginia, who had been funded by the National Institute of Health to find evidence that marijuana damages the immune system, found instead that THC slowed the growth of three kinds of cancer in mice — lung and breast cancer, and a virus-induced leukemia. The DEA quickly shut down the Virginia study and all further cannabis/tumor research, according to Jack Herer, who reports on the events in his book, “The Emperor Wears No Clothes.” In 1976 President Gerald Ford put an end to all public cannabis research and granted exclusive research rights to major pharmaceutical companies, who set out — unsuccessfully — to develop synthetic forms of THC that would deliver all the medical benefits without the “high.” The Madrid researchers reported in the March issue of “Nature Medicine” that they injected the brains of 45 rats with cancer cells, producing tumors whose presence they confirmed through magnetic resonance imaging (MRI). On the 12th day they injected 15 of the rats with THC and 15 with Win-55,212-2 a synthetic compound similar to THC. “All the rats left untreated uniformly died 12-18 days after glioma (brain cancer) cell inoculation … Cannabinoid (THC)-treated rats survived significantly longer than control rats. THC administration was ineffective in three rats, which died by days 16-18. Nine of the THC-treated rats surpassed the time of death of untreated rats, and survived up to 19-35 days. Moreover, the tumor was completely eradicated in three of the treated rats.” The rats treated with Win-55,212-2 showed similar results. The Spanish researchers, led by Dr. Manuel Guzman of Complutense University, also irrigated healthy rats’ brains with large doses of THC for seven days, to test for harmful biochemical or neurological effects. They found none. “Careful MRI analysis of all those tumor-free rats showed no sign of damage related to necrosis, edema, infection or trauma … We also examined other potential side effects of cannabinoid administration. In both tumor-free and tumor-bearing rats, cannabinoid administration induced no substantial change in behavioral parameters such as motor coordination or physical activity. Food and water intake as well as body weight gain were unaffected during and after cannabinoid delivery. Likewise, the general hematological profiles of cannabinoid-treated rats were normal. Thus, neither biochemical parameters nor markers of tissue damage changed substantially during the 7-day delivery period or for at least 2 months after cannabinoid treatment ended.” Guzman’s investigation is the only time since the 1974 Virginia study that THC has been administered to live tumor-bearing animals. (The Spanish researchers cite a 1998 study in which cannabinoids inhibited breast cancer cell proliferation, but that was a “petri dish” experiment that didn’t involve live subjects.) In an email interview for this story, the Madrid researcher said he had heard of the Virginia study, but had never been able to locate literature on it. Hence, the Nature Medicine article characterizes the new study as the first on tumor-laden animals and doesn’t cite the 1974 Virginia investigation. “I am aware of the existence of that research. In fact I have attempted many times to obtain the journal article on the original investigation by these people, but it has proven impossible.” Guzman said. In 1983 the Reagan/Bush Administration tried to persuade American universities and researchers to destroy all 1966-76 cannabis research work, including compendiums in libraries, reports Jack Herer, who states, “We know that large amounts of information have since disappeared.” Guzman provided the title of the work — “Antineoplastic activity of cannabinoids,” an article in a 1975 Journal of the National Cancer Institute — and this writer obtained a copy at the University of California medical school library in Davis and faxed it to Madrid. The summary of the Virginia study begins, “Lewis lung adenocarcinoma growth was retarded by the oral administration of tetrahydrocannabinol (THC) and cannabinol (CBN)” — two types of cannabinoids, a family of active components in marijuana. “Mice treated for 20 consecutive days with THC and CBN had reduced primary tumor size.” The 1975 journal article doesn’t mention breast cancer tumors, which featured in the only newspaper story ever to appear about the 1974 study — in the Local section of the Washington Post on August 18, 1974. Under the headline, “Cancer Curb Is Studied,” it read in part: “The active chemical agent in marijuana curbs the growth of three kinds of cancer in mice and may also suppress the immunity reaction that causes rejection of organ transplants, a Medical College of Virginia team has discovered.” The researchers “found that THC slowed the growth of lung cancers, breast cancers and a virus-induced leukemia in laboratory mice, and prolonged their lives by as much as 36 percent.” Guzman, writing from Madrid, was eloquent in his response after this writer faxed him the clipping from the Washington Post of a quarter century ago. In translation, he wrote: “It is extremely interesting to me, the hope that the project seemed to awaken at that moment, and the sad evolution of events during the years following the discovery, until now we once again Œdraw back the veil‚ over the anti-tumoral power of THC, twenty-five years later. Unfortunately, the world bumps along between such moments of hope and long periods of intellectual castration.” News coverage of the Madrid discovery has been virtually nonexistent in this country. The news broke quietly on Feb. 29, 2000 with a story that ran once on the UPI wire about the Nature Medicine article. This writer stumbled on it through a link that appeared briefly on the Drudge Report web page. The New York Times, Washington Post and Los Angeles Times all ignored the story, even though its newsworthiness is indisputable: a benign substance occurring in nature destroys deadly brain tumors. http://www.alternet.org/story/9257/pot_shrinks_tumors%3B_government_knew_in_’74

Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation.

“Here, we show that Δ⁹-tetrahydrocannabinol (THC), through activation of CB₂ cannabinoid receptors, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis.” “..these data might set the bases for a cannabinoid therapy for the management of breast cancer.” http://cancerres.aacrjournals.org/content/66/13/6615.full.html

Cannabidiol inhibits tumour growth in leukaemia and breast cancer in animal studies:

“Cannabidiol (CBD) was the most potent cannabinoid in inhibiting the growth of human breast cancer cells that had been injected under the skin of mice. CBD also reduced lung metastases deriving from human breast cancer cells that had been injected into the paws of the animals.” “Researchers found that the anti-tumour effects of CBD were caused by induction of apoptosis (programmed cell death). They concluded that their data “support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer. These observations are supported by investigations of US scientists who found out that exposure of leukaemia cells to CBD led to a reduction in cell viability and induction of apoptosis. In living animals CBD caused a reduction in number of leukaemia cells. The scientists noted that CBD “may be a novel and highly selective treatment for leukemia.” http://www.cannabis-med.org/english/bulletin/ww_en_db_cannabis_artikel.php?id=220 http://www.cannabis-med.org/english/bulletin/ww_en_db_cannabis_artikel.php?id=220#2 

Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation.:

“These findings suggest that endogenous cannabinoids and CB1 receptor agonists are potential negative effectors of PRL- and NGF-induced biological responses, at least in some cancer cells.” http://press.endocrine.org/doi/abs/10.1210/endo.141.1.7239 

The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation:

“These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor.” http://www.ncbi.nlm.nih.gov/pubmed/16099783 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774787/

Pot Slows Cancer in Test Tube

Marijuana Ingredients Slow Invasion by Cervical and Lung Cancer Cells

Ingredients Found in Cannabis slow the spread of cervical and lung cancers, test-tube studies suggest. “Might cannabinoids keep dangerous tumors from spreading throughout the body? Ramer and Hinz set up an experiment in which invasive cervical and lung cancer cells had make their way through a tissue-like gel. Even at very low concentrations, the marijuana compounds THC and methanandamide (MA) significantly slowed the invading cancer cells.” Pot Slows Cancer in Test Tube – WebMD

Cannabinoids in intestinal inflammation and cancer.:

“Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of the endocannabinoid system have been observed in intestinal biopsies from patients with inflammatory bowel disease and colon cancer. Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing. In vivo, cannabinoids – via direct or indirect activation of CB(1) and/or CB(2) receptors – exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.” http://www.ncbi.nlm.nih.gov/pubmed/19442536

Cannabis compound clue to colon cancer:

“One suggestion is that lack of CB1 encourages tumour growth because the receptor normally interacts with cannabinoids made by the body to prompt cells to die. This opens up a possible two-step treatment for colon cancer.” http://www.newscientist.com/article/mg19926685.000-cannabis-compound-clue-to-colon-cancer.html?feedId=drugs-alcohol_rss20

Marijuana takes on colon cancer:

“The chemicals in marijuana could put the brakes on colon cancer, according to new research.” “Raymond DuBois and colleagues at the University of Texas in Houston discovered that a key receptor for cannabinoids, which are found in marijuana, is turned off in most types of human colon cancer.” “”When we knocked out the receptor, the number of tumors went up dramatically,” says DuBois. Alternatively, when mice with normal CB1 receptors were treated with a cannabinoid compound, their tumours shrank.” http://www.newscientist.com/article/dn14451-marijuana-takes-on-colon-cancer.html?DCMP=ILC-hmts&nsref=news9_head_dn14451

The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2:

“These findings suggest anandamide may be a useful chemopreventive/therapeutic agent for colorectal cancer as it targets cells that are high expressors of COX-2, and may also be used in the eradication of tumour cells that have become resistant to apoptosis.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774787/

Anti-Tumor Effects:

“Emerging research indicates that cannabinoids may help protect against the development of certain types of tumors. Most recently, a Spanish research team reported in Nature that injections of synthetic THC eradicated malignant brain tumors – so-called gliomas – in one-third of treated rats, and prolonged life in another third by as much as six weeks. “ “Earlier studies also indicate that cannabinoids may successfully stave certain types of tumors. One study examined the effects of delta-9-tetrahydrocannabinol (THC), delta-8-THC, and cannabinol (CBN) on cancer cells in mice lungs. Researchers reported that cannabinoids reduced the size of the tumors by 25 to 82 percent, depending on dose and duration of treatment, with a corresponding increase in survival time. (8) A two-year federal study by the U.S. National Toxicology Program found that mice and rats given high doses of THC over long periods of time appeared to have greater protection against malignancies than untreated controls. Researchers concluded that in both mice and rats, “the incidence of benign and malignant neoplasms was decreased in a dose dependent manner.”” “An Italian research team reported in 1998 that the endocannabinoid anandamide, which binds to the same brain receptors as cannabis, “potently and selectively inhibits the proliferation of human breast cancer cells in vitro” by interfering with their DNA production cycle. (12,13) Non-mammary tumor cells were not affected by anandamide. Clearly, further research is necessary and appropriate.” http://www.ukcia.org/research/AntiTumorEffects.php

Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism:

“These results reinforce the evidence of antitumoral properties of CBD, demonstrating its ability to limit tumor invasion,..” “Numerous recent reports state that cannabinoids inhibit the viability of various types of cancer cells in vitro and in vivo (Parolaro et al., 2002; Guzman, 2003). Cannabinoids induce apoptosis of malignant glioma cells, that is, from the most common primary cerebral tumor in adults.” “In conclusion, the present study demonstrates, for the first time, that CBD can inhibit the migration of tumoral cells…” “..Our data further support the use of cannabinoids as antimetastatic drugs as previously demonstrated for met-fluoro-anandamide on rat thyroid cancer cell (Portella et al., 2003). This antimigratory property, together with the known antiproliferative and apoptotic features of CBD (Massi et al., 2004), strengthen the evidence for its use as a potential antitumoral agent.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1576089/

Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells:

“Here we demonstrate that Δ9-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3–dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673842/

Cannabinoids Inhibit the Vascular Endothelial Growth Factor Pathway in Gliomas:

“Here, we report that cannabinoid administration inhibits the VEGF pathway in cultured glioma cells, in glioma-bearing mice, and in two patients with glioblastoma multiforme. In addition, this effect may be mediated by ceramide, a sphingolipid second messenger implicated previously in cannabinoid signaling in glioma cells “ “..intratumoral administration of the cannabinoid Δ⁹-tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels and VEGFR-2 activation in the tumors. Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.” http://cancerres.aacrjournals.org/content/64/16/5617.full

Cannabis phytochemical shown to shrink brain tumors:

“Researchers in Spain have discovered that a cannabis extract makes brain tumors shrink by halting the growth of blood vessels that supply the tumors with life. ” “Cannabis has chemicals called cannabinoids, these are the chemicals that could effectively starve tumors to death, say the researchers.” http://www.naturalnews.com/002575_cannabis_medical_marijuana.html Medical News Today, see also as: Cannabis extract makes brain tumors shrink, halts growth of blood vessels: http://www.medicalnewstoday.com/releases/12088.php 

A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme:

“The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids” http://www.ncbi.nlm.nih.gov/pubmed/16804518

WIN induces apoptotic cell death in human colon cancer cells through a block of autophagic flux dependent on PPARγ down-regulation.

“Cannabinoids have been reported to possess anti-tumorigenic activity in cancer models although their mechanism of action is not well understood. Here, we show that the synthetic cannabinoid WIN55,212-2 (WIN)-induced apoptosis in colon cancer cell lines is accompanied by endoplasmic reticulum stress induction. ” http://www.ncbi.nlm.nih.gov/pubmed/24696378

More Archived Cannabinoid & Cancer research and studies from around the world:

Pharmacokinetics and pharmacodynamics of cannabinoids.:

“Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.” http://www.ncbi.nlm.nih.gov/pubmed/12648025

Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1.

“..these findings provide a novel mechanism underlying the anti-invasive action of cannabidiol and imply its use as a therapeutic option for the treatment of highly invasive cancers.” http://www.ncbi.nlm.nih.gov/pubmed/19914218

Up-regulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide-induced apoptotic death of human neuroglioma cells.:

“Cannabinoids have been implicated in the reduction of glioma growth…” “As a whole, this study defines COX-2 as a hitherto unknown target by which a cannabinoid induces apoptotic death of glioma cells.” http://www.ncbi.nlm.nih.gov/pubmed/15361550

Antitumorigenic Effects of Cannabinoids beyond Apoptosis

“…This review will summarize the data concerning the influence of cannabinoids on these locomotive processes beyond modulation of cancer cell apoptosis and proliferation. The findings discussed here provide a new perspective on the antitumorigenic potential of cannabinoids.” http://www.ncbi.nlm.nih.gov/pubmed/19889794

R(+)-methanandamide-induced apoptosis of human cervical carcinoma cells involves a cyclooxygenase-2-dependent pathway.

“Cannabinoids have received renewed interest due to their antitumorigenic effects. Using human cervical carcinoma cells (HeLa), this study investigates the role of cyclooxygenase-2 (COX-2) in apoptosis elicited by the endocannabinoid analog R(+)-methanandamide (MA)…” “..A role of COX-2 and PPARgamma in MA-induced apoptosis was confirmed in another human cervical cancer cell line (C33A) and in human lung carcinoma cells (A549).” http://www.ncbi.nlm.nih.gov/pubmed/19015962

The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities:

“The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease…” “..It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757311/

HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor.

“..A new anticancer quinone (HU-331) was synthesized from cannabidiol. It shows significant high efficacy against human cancer cell lines in vitro and against in vivo tumor grafts in nude mice…” “..HU-331-caused cell death of human cancer cell lines is not mediated by reactive oxygen intermediates/species, as exposure to HU-331 failed to elicit the generation of reactive oxygen species…” “It might represent a new potent anticancer drug.” http://www.ncbi.nlm.nih.gov/pubmed/17237277

Gamma-irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells.

“Two non-psychotropic cannabinoids, cannabidiol (CBD) and cannabidiol-dimethylheptyl (CBD-DMH), induced apoptosis in a human acute myeloid leukemia (AML) HL-60 cell line…” “..Caspase-3 activation was observed after the cannabinoid treatment, and may represent a mechanism for the apoptosis. Our data suggest a possible new approach to treatment of AML.” http://www.ncbi.nlm.nih.gov/pubmed/14692532

A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells.

“We have reported that a new cannabinoid anticancer quinone, cannabidiol hydroxyquinone (HU-331), is highly effective against tumor xenografts in nude mice…” …The ability of cannabinoids to cause endothelial cell apoptosis was assayed by TUNEL staining and flow cytometry analysis… “..A significant decrease in the total area occupied by vessels in HU-331-treated tumors was also observed. These data lead us to consider HU-331 to have high potential as a new antiangiogenic and anticancer drug.” http://www.ncbi.nlm.nih.gov/pubmed/16571653

Cannabinoids in health and disease

“..the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, Alzheimer’s disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable…” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202504/

Cannabinoids and cancer.

“..Marijuana has been used in medicine for millennia,…” “In 1975, Munson discovered that cannabinoids suppress Lewis lung carcinoma cell growth. The mechanism of this action was shown to be inhibition of DNA synthesis. Antiproliferative action on some other cancer cells was also found. In spite of the promising results from these early studies…” “..Di Marzo’s group found that cannabinoids inhibit breast cancer cell proliferation, and Guzman’s group found that cannabinoids inhibit the growth of C6 glioma cell. Other groups also started work in this field, and today, a wide array of cancer cell lines that are affected is known, and some mechanisms involved have been elucidated.”
http://www.ncbi.nlm.nih.gov/pubmed/16250836

Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells.

“The active components of Cannabis sativa L., Cannabinoids, traditionally used in the field of cancer for alleviation of pain, nausea, wasting and improvement of well-being have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory activity and induction of tumor regression. Here we used several experimental approaches, which identified delta-9-tetrahydrocannabinol (Delta(9)-THC) as an essential mediator of cannabinoid antitumoral action.” “..Delta(9)-THC is shown to significantly affect viability of GBM cells via a mechanism that appears to elicit G(1) arrest due to downregulation of E2F1 and Cyclin A. Hence, it is suggested that Delta(9)-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors…” http://www.ncbi.nlm.nih.gov/pubmed/17934890

Endocannabinoids in the immune system and cancer.

“The present review focuses on the role of the endogenous cannabinoid system in the modulation of immune response and control of cancer cell proliferation” http://www.ncbi.nlm.nih.gov/pubmed/12052046

A metabolically stable analogue of anandamide, Met-F-AEA, inhibits human thyroid carcinoma cell lines by activation of apoptosis.

“We analysed the effects exerted by 2-methyl-2′-F-anandamide (Met-F-AEA), a metabolically stable analogue of anandamide, and observed a growth inhibition in cell lines derived from thyroid carcinomas. Growth inhibition was associated with a high level of CB1 receptor expression, suggesting that the cytotoxic effect is due to interaction with the CB1 receptor.“ “..significance in providing a basis for the management of thyroid carcinoma….” http://www.ncbi.nlm.nih.gov/pubmed/19189054

Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8.

“Our findings suggest that phytocannabinoids and cannabis extracts exert some of their pharmacological actions also by interacting with TRPA1 and TRPM8 channels, with potential implications for the treatment of pain and cancer.” http://www.ncbi.nlm.nih.gov/pubmed/18354058

Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells

“The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-alpha acts as a link between cannabinoid receptor activation and ceramide production.” http://clincancerres.aacrjournals.org/content/14/23/7691.short http://www.ncbi.nlm.nih.gov/pubmed/19047095

Anandamide Induces Apoptosis in Human Cells via Vanilloid Receptors EVIDENCE FOR A PROTECTIVE ROLE OF CANNABINOID RECEPTORS*

“The endocannabinoid anandamide (AEA) is shown to induce apoptotic bodies formation and DNA fragmentation, hallmarks of programmed cell death, in human neuroblastoma CHP100 and lymphoma U937 cells.” http://www.ncbi.nlm.nih.gov/pubmed/10913156

The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

“Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro. “ “These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC20983/

Cannabinoids as potential new therapy for the treatment of gliomas.

“A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects, and may set the basis for further studies aimed at better evaluating the potential anticancer activity of cannabinoids.” http://www.ncbi.nlm.nih.gov/pubmed/18088200

The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells

“Recently, we have shown that the non-psychoactive cannabinoid compound cannabidiol (CBD) induces apoptosis of glioma cells in vitro and tumor regression in vivo.” http://www.ncbi.nlm.nih.gov/pubmed/16909207

Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review).

“There is increasing evidence that endocannabinoids are able to inhibit cancer cell growth in culture as well as in animal models. Most work has focused on the role of endocannabinoids in regulating tumor cell growth and apoptosis and ongoing research is addressed to further dissect the precise mechanisms of cannabinoid antitumor action. However, endocannabinoids are now emerging as suppressors of angiogenesis and tumor spreading since they have been reported to inhibit angiogenesis, cell migration and metastasis in different types of cancer, pointing to a potential role of the endocannabinoid system as a target for a therapeutic approach of such malignant diseases. The potential use of cannabinoids to retard tumor growth and spreading is even more appealing considering that they show a good safety profile, regarding toxicity, and are already used in cancer patients as palliatives to stimulate appetite and to prevent devastating effects such as nausea, vomiting and pain.” http://www.ncbi.nlm.nih.gov/pubmed/17342320

Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: involvement of the transcription factor PPARgamma.

“It has recently been shown that cannabinoids induce growth inhibition and apoptosis in different tumour cell lines.” “..WIN-induced apoptosis is associated with JNK/p38 MAPK pathway activation and mitochondrial depolarisation demonstrated by a cytofluorimetric assay. “ “Altogether, the results seem to indicate a potential therapeutic role of WIN in hepatic cancer treatment.” http://www.ncbi.nlm.nih.gov/pubmed/19059457

[The endocannabinoid system as a target for the development of new drugs for cancer therapy].

“Recently, evidence has accumulated indicating that stimulation of cannabinoid receptors by either THC or the endocannabinoids influence the intracellular events controlling the proliferation and apoptosis of numerous types of cancer cells, thereby leading to anti-tumour effects both in vitro and in vivo. This evidence is reviewed here and suggests that future anti-cancer therapy might be developed from our knowledge of how the endocannabinoid system controls the growth and metastasis of malignant cells.” http://www.ncbi.nlm.nih.gov/pubmed/12723496

Cannabinoids in intestinal inflammation and cancer.

“Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of the endocannabinoid system have been observed in intestinal biopsies from patients with inflammatory bowel disease and colon cancer. Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing. In vivo, cannabinoids – via direct or indirect activation of CB(1) and/or CB(2) receptors – exert protective effects in well-established models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promising strategy to counteract intestinal inflammation and colon cancer.” http://www.ncbi.nlm.nih.gov/pubmed/19442536

Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma.

“The cannabidiol-rich extract was equipotent to cannabidiol, whereas cannabigerol and cannabichromene followed in the rank of potency. Both cannabidiol and the cannabidiol-rich extract inhibited the growth of xenograft tumors obtained by s.c. injection into athymic mice of human MDA-MB-231 breast carcinoma or rat v-K-ras-transformed thyroid epithelial cells and reduced lung metastases deriving from intrapaw injection of MDA-MB-231 cells.” “our experiments indicate that cannabidiol effect is due to its capability of inducing apoptosis via: direct or indirect activation of cannabinoid CB₂ and vanilloid transient receptor potential vanilloid type-1 receptors and cannabinoid/vanilloid receptor-independent elevation of intracellular Ca²⁺ and reactive oxygen species. Our data support the further testing of cannabidiol and cannabidiol-rich extracts for the potential treatment of cancer.” http://www.ncbi.nlm.nih.gov/pubmed/16728591

The CB1/CB2 receptor agonist WIN-55,212-2 reduces viability of human Kaposi’s sarcoma cells in vitro.

“The CB(2) receptor antagonist AM630 was able to significantly increase survival of Kaposi’s sarcoma cells treated with WIN. In view of the antiproliferative effects of cannabinoids on KS-IMM cells, one could envision the cannabinoid system as a potential target for pharmacological treatment of Kaposi’s sarcoma.” http://www.ncbi.nlm.nih.gov/pubmed/19539619

Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism.

“Cannabinoids (CBs) are implicated in the control of cell survival in different types of tumors,..” “Our results demonstrate that CBs produce a significant cytotoxic effect via a receptor-independent mechanism” http://www.ncbi.nlm.nih.gov/pubmed/16500647

The endocannabinoid anandamide neither impairs in vitro T-cell function nor induces regulatory T-cell generation.

“The cannabinoids have been proposed in the treatment of cancer. Generally, the cannabinoids are believed to be useful only in the palliative therapy of cancer-related symptoms, namely pain, anorexia and cachexia. However, preliminary experiments would also suggest an inhibitory effect of cannabinoids on cancer growth,..” “The direct antitumor activity of AEA together with the absence of negative effects on T-cell functions might provide new insights into the potential use of cannabinoid agents in cancer immunotherapy.” http://www.ncbi.nlm.nih.gov/pubmed/19189659

Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines.

“Recently, cannabinoids (CBs) have been shown to possess antitumor properties.” “We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.” http://www.ncbi.nlm.nih.gov/pubmed/14617682

Estrogenic induction of cannabinoid CB1 receptor in human colon cancer cell lines.

“CB1 receptor is a G-protein-coupled receptor that is linked to the signal transduction pathways. The cumulative effects of this receptor have important implications in the control of cell survival and cell death having the potential to regulate tumor cell growth” “..Up-regulation of CB1 expression by 17beta-estradiol is a further mechanism of estrogens to control colon cancer proliferation.” http://www.ncbi.nlm.nih.gov/pubmed/18938775

Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders.

“Studies aimed at correlating the tissue and body fluid levels of endogenous cannabinoid-like molecules with pathological conditions have been started and may lead to identify those diseases that can be alleviated by drugs that either mimic or antagonize the action of these substances, or modulate their biosynthesis and degradation” “In this article, we discuss the anti-tumor and anti-inflammatory activity of: (1) the endocannabinoids anandamide (arachidonoylethanolamide) and 2-arachidonoyl glycerol; (2) the bioactive fatty acid amides palmitoylethanolamide and oleamide; and (3) some synthetic derivatives of these compounds, such as the N-acyl-vanillyl-amines. Furthermore, the possible role of cannabimimetic fatty acid derivatives in the pathological consequences of cancer and inflammation, such as cachexia, wasting syndrome, chronic pain and local vasodilation, will be examined.” http://www.ncbi.nlm.nih.gov/pubmed/11106791

Pharmacological synergism between cannabinoids and paclitaxel in gastric cancer cell lines.

“In this study, we investigated how the endogenous cannabinoid anandamide (AEA) changes the effect of paclitaxel on gastric cancer cell lines” “Our results suggest that cannabinoids could be a good palliative agent for cancer patients receiving paclitaxel.” http://www.ncbi.nlm.nih.gov/pubmed/19394652

Effect of a synthetic cannabinoid agonist on the proliferation and invasion of gastric cancer cells.

“The cannabinoid agonist WIN 55,212-2 inhibited the proliferation of human gastric cancer cells in a dose-dependent manner and that this effect was mediated partially by the CB(1) receptor. We also found that WIN 55,212-2 induced apoptosis and down-regulation of the phospho-AKT expression in human gastric cancer cells. Furthermore, WIN 55,212-2 treatment inhibited the invasion of gastric cancer cells, and down-regulated the expression of MMP-2 and VEGF-A through the cannabinoid receptors. Our results open the possibilities in using cannabinoids as a new gastric cancer therapy.” http://www.ncbi.nlm.nih.gov/pubmed/20336665

Cannabinoids in the treatment of cancer.

“Cannabinoids, the active components of the hemp plant Cannabis sativa, along with their endogenous counterparts and synthetic derivatives, have elicited anti-cancer effects in many different in vitro and in vivo models of cancer. While the various cannabinoids have been examined in a variety of cancer models, recent studies have focused on the role of cannabinoid receptor agonists (both CB(1) and CB(2)) in the treatment of estrogen receptor-negative breast cancer. This review will summarize the anti-cancer properties of the cannabinoids,..” http://www.ncbi.nlm.nih.gov/pubmed/19442435

Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of Bad protein.

“Thus, we suggest that the increase of proapoptotic Bad activity is an important link between the inhibition of survival pathways and an onset of execution phase of cannabinoid-induced glioma cell death.” http://www.ncbi.nlm.nih.gov/pubmed/15451022

Cannabinoid 2 receptor induction by IL-12 and its potential as a therapeutic target for the treatment of anaplastic thyroid carcinoma.

“Given that cannabinoids have shown antitumor effects in many types of cancer models, CB2 may be a viable therapeutic target for the treatment of anaplastic thyroid carcinoma.” http://www.ncbi.nlm.nih.gov/pubmed/18197164

[Different views on the association between cannabinoids and cancer].

“The important function of endocannabinoids which is related to cancer, is the regulation of cell cycle and cell survival pathways. Presented review gives three different views on the association between cannabinoids and cancer. First, the treatment of adverse symptoms of oncological therapy – nausea and vomiting inhibition, appetite stimulation, pain relieving, mood modulation and muscle stiffness relieving. Second, in the late 1990s, three possible mechanisms of antitumour action were identified – apoptosis induction, direct cell cycle arrest and angiogenesis and metastasis inhibition. The phase I/II of clinical trials are carrying out in Spain. They study effects of local administration of tetrahydrokanabinol on the growth of glioblastoma multiforme. Third, the results of the newest study focused on the association between cannabinoids use and cancer risk showed no significant association between increased cancer incidence and cannabinoids use and it does not depend on the amount of used cannabis.” http://www.ncbi.nlm.nih.gov/pubmed/16835997

 

De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis.

“Delta(9)-Tetrahydrocannabinol (THC) and other cannabinoids have been shown to induce apoptosis of glioma cells via ceramide generation.” “These findings show that de novo-synthesized ceramide is involved in cannabinoid-induced apoptosis of glioma cells.” http://www.ncbi.nlm.nih.gov/pubmed/11903061

Down-regulation of tissue inhibitor of metalloproteinases-1 in gliomas: a new marker of cannabinoid antitumoral activity?

“Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and inhibiting tumor angiogenesis. It has also been reported that cannabinoids inhibit tumor cell invasiveness,..” “TIMP-1 down-regulation may be a hallmark of cannabinoid-induced inhibition of glioma progression.” http://www.ncbi.nlm.nih.gov/pubmed/17675107

Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis.

“Cannabinoids are known to exert an antitumoral action on gliomas that relies on at least two mechanisms: induction of apoptosis of transformed cells and inhibition of tumor angiogenesis. “ “Overall, our results demonstrate that cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in the management of malignant gliomas.” http://www.ncbi.nlm.nih.gov/pubmed/17202146

Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells

“These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.” http://www.ncbi.nlm.nih.gov/pubmed/19425170

JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells.

“..this is the first report showing not only that cannabinoids regulate JunD but, more generally, that JunD activation reduces the proliferation of cancer cells, which points to a new target to inhibit breast cancer progression.” http://www.ncbi.nlm.nih.gov/pubmed/18454173

Cannabinoid receptors as novel targets for the treatment of melanoma.

“Cannabinoid antimelanoma activity was independent of the immune status of the animal, could be achieved without overt psychoactive effects and was selective for melanoma cells vs. normal melanocytes. Cannabinoid antiproliferative action on melanoma cells was due, at least in part, to cell cycle arrest at the G1-S transition via inhibition of the prosurvival protein Akt and hypophosphorylation of the pRb retinoblastoma protein tumor suppressor. These findings may contribute to the design of new chemotherapeutic strategies for the management of melanoma.” http://www.ncbi.nlm.nih.gov/pubmed/17065222

Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation.

“Experiments with two subclones of C6 glioma cells in culture showed that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors, sustained ceramide accumulation and Raf1/extracellular signal-regulated kinase activation. These results may provide the basis for a new therapeutic approach for the treatment of malignant gliomas.” http://www.ncbi.nlm.nih.gov/pubmed/10700234

Cannabinoids and ceramide: two lipids acting hand-by-hand.

“Sustained ceramide accumulation in tumor cells mediates cannabinoid-induced apoptosis, as evidenced by in vitro and in vivo studies. This effect seems to be due to the impact of ceramide on key cell signalling systems such as the extracellular signal-regulated kinase cascade and the Akt pathway. These findings provide a new conceptual view on how cannabinoids act….” http://www.ncbi.nlm.nih.gov/pubmed/15958274

p38 MAPK is involved in CB2 receptor-induced apoptosis of human leukaemia cells.

“Cannabinoids have been shown to inhibit the growth of a broad spectrum of tumour cells. “ “Here, we investigated the possible involvement of mitogen-activated protein kinases (MAPKs) in CB2 receptor-induced apoptosis of human leukaemia cells. Results show that stimulation of the CB2 receptor leads to p38 MAPK activation and that inhibition of this kinase attenuates CB2 receptor-induced caspase activation and apoptosis. These findings support a role for p38 MAPK in CB2 receptor-induced apoptosis of human leukaemia cells.” http://www.ncbi.nlm.nih.gov/pubmed/16139274

The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway.

“Delta9-tetrahydrocannabinol and other cannabinoids exert pro-apoptotic actions in tumor cells via the CB2 cannabinoid receptor.” “In summary, results presented here show that CB2 receptor activation signals apoptosis via a ceramide-dependent stimulation of the mitochondrial intrinsic pathway.” http://www.ncbi.nlm.nih.gov/pubmed/16624285

The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells.

“One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs.” “We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes ATF-4, CHOP, and TRB3. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.” http://www.ncbi.nlm.nih.gov/pubmed/16616335

Control of the cell survival/death decision by cannabinoids.

“One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and non neural cells” “..cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells. The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined.” “Regarding the central nervous system, most of the experimental evidence indicates that cannabinoids may protect neurons from toxic insults such as glutamaergic overstimulation, ischemia and oxidative damage. In contrast, cannabinoids induce apoptosis of glioma cells in culture and regression of malignant gliomas in vivo. Breast and prostate cancer cells are also sensitive to cannabinoid-induced anti proliferation” “The neuroprotective effect of cannabinoids may have potential clinical relevance for the treatment of neurodegenerative disorders such as multiple sclerosis, Parkinson’s disease, and ischemia/stroke, whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant brain tumors. “ http://www.ncbi.nlm.nih.gov/pubmed/11269508

Established and potential therapeutic applications of cannabinoids in oncology.

” Recently, there has been renewed interest in cannabinoids for medicinal purposes. The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia.” http://www.ncbi.nlm.nih.gov/pubmed/12618922

Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2

“This study defines the involvement of CB2-mediated signalling in the in vivo and in vitro growth inhibition of prostate cancer cells and suggests that CB2 agonists have potential therapeutic interest and deserve to be explored in the management of prostate cancer.” http://www.nature.com/bjc/journal/v101/n6/abs/6605248a.html http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743360/

Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors

“Nonmelanoma skin cancer is one of the most common malignancies in humans…” “The present data indicate that local cannabinoid administration may constitute an alternative therapeutic approach for the treatment of nonmelanoma skin cancer. Of further therapeutic interest, we show that skin cells express functional CB2 receptors. The synergy between CB1 and CB2 receptors in eliciting skin tumor cell apoptosis reported here is nonetheless intriguing because it is not observed in the case of cannabinoid-induced glioma cell apoptosis (21, 22). In any event, the present report, together with the implication of CB2- or CB2-like receptors in the control of peripheral pain (40–42) and inflammation (41), opens the attractive possibility of finding cannabinoid-based therapeutic strategies for diseases of the skin and other tissues devoid of nondesired CB1-mediated psychotropic side effects.” http://www.ncbi.nlm.nih.gov/pubmed/12511587

Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas.

“During the last years, several studies have demonstrated that cannabinoids induce apoptosis of glioma cells and inhibit angiogenesis of gliomas in vivo.” “The present results demonstrate opposite changes in CB(1) and CB(2) receptor protein expression in human gliomas. These changes may be of interest for further research about the therapeutic effects of cannabinoids in glial tumors.” http://www.ncbi.nlm.nih.gov/pubmed/20307616

Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation.

“Here, we show that Delta(9)-tetrahydrocannabinol (THC), through activation of CB(2) cannabinoid receptors, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis. In particular, THC arrests cells in G(2)-M via down-regulation of Cdc2, as suggested by the decreased sensitivity to THC acquired by Cdc2-overexpressing cells. Of interest, the proliferation pattern of normal human mammary epithelial cells was much less affected by THC.” “We found a correlation between CB(2) expression and histologic grade of the tumors. There was also an association between CB(2) expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor, and ERBB2/HER-2 oncogene. Importantly, no significant CB(2) expression was detected in nontumor breast tissue. Taken together, these data might set the bases for a cannabinoid therapy for the management of breast cancer.” http://www.ncbi.nlm.nih.gov/pubmed/16818634

Cannabinoids and gliomas.

“Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.” http://www.ncbi.nlm.nih.gov/pubmed/17952650

Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes.

“Pancreatic adenocarcinomas are among the most malignant forms of cancer and, therefore, it is of especial interest to set new strategies aimed at improving the prognostic of this deadly disease.” “Studies conducted with MiaPaCa2 and Panc1 cell lines showed that cannabinoid administration (a) induced apoptosis, (b) increased ceramide levels, and (c) up-regulated mRNA levels of the stress protein p8. These effects were prevented by blockade of the CB(2) cannabinoid receptor or by pharmacologic inhibition of ceramide synthesis de novo. Knockdown experiments using selective small interfering RNAs showed the involvement of p8 via its downstream endoplasmic reticulum stress-related targets activating transcription factor 4 (ATF-4) and TRB3 in Delta(9)-tetrahydrocannabinol-induced apoptosis. Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading of pancreatic tumor cells. Moreover, cannabinoid administration selectively increased apoptosis and TRB3 expression in pancreatic tumor cells but not in normal tissue. In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB(2) receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress-related genes ATF-4 and TRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreatic cancer.” http://www.ncbi.nlm.nih.gov/pubmed/16818650

Effects on cell viability.

“The findings reviewed here might set the basis for the use of cannabinoids in the treatment of cancer and neurodegenerative diseases.” http://www.ncbi.nlm.nih.gov/pubmed/16596790

Involvement of cannabinoids in cellular proliferation.

“The capacity of endogenous and synthetic cannabinoids to induce apoptosis of different tumoral cells in culture and in vivo, the mechanism underlying and the potential therapeutic applications are discussed in this review.”http://www.ncbi.nlm.nih.gov/pubmed/15638794

Hypothesis: cannabinoid therapy for the treatment of gliomas?

“Gliomas, in particular glioblastoma multiforme or grade IV astrocytoma, are the most frequent class of malignant primary brain tumours and one of the most aggressive forms of cancer.” “During the last few years, several studies have shown that cannabinoids-the active components of the plant Cannabis sativa and their derivatives–slow the growth of different types of tumours, including gliomas, in laboratory animals. Cannabinoids induce apoptosis of glioma cells in culture via sustained ceramide accumulation, extracellular signal-regulated kinase activation and Akt inhibition. In addition, cannabinoid treatment inhibits angiogenesis of gliomas in vivo. Remarkably, cannabinoids kill glioma cells selectively and can protect non-transformed glial cells from death. These and other findings reviewed here might set the basis for a potential use of cannabinoids in the management of gliomas.” http://www.ncbi.nlm.nih.gov/pubmed/15275820

Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway.

“Here we used the pro-apoptotic lipid ceramide to induce apoptosis in astrocytes, and we studied the protective effect exerted by cannabinoids. Results show the following: (i) cannabinoids rescue primary astrocytes from C(2)-ceramide-induced apoptosis in a dose- and time-dependent manner; (ii) triggering of this anti-apoptotic signal depends on the phosphatidylinositol 3-kinase/protein kinase B pathway; (iii) ERK and its downstream target p90 ribosomal S6 kinase might be also involved in the protective effect of cannabinoids; and (iv) cannabinoids protect astrocytes from the cytotoxic effects of focal C(2)-ceramide administration in vivo. In summary, results show that cannabinoids protect astrocytes from ceramide-induced apoptosis via stimulation of the phosphatidylinositol 3-kinase/protein kinase B pathway. These findings constitute the first evidence for an “astroprotective” role of cannabinoids.” http://www.ncbi.nlm.nih.gov/pubmed/12133838

Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression.

“Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and impairing tumor angiogenesis. It has also been reported that these compounds inhibit tumor cell spreading, ..” “Local administration of Delta(9)-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down-regulated MMP-2 expression in gliomas generated in mice, as determined by Western blot, immunofluorescence, and real-time quantitative PCR analyses. This cannabinoid-induced inhibition of MMP-2 expression in gliomas (a) was MMP-2-selective, as levels of other MMP family members were unaffected; (b) was mimicked by JWH-133, a CB(2) cannabinoid receptor-selective agonist that is devoid of psychoactive side effects; (c) was abrogated by fumonisin B1, a selective inhibitor of ceramide biosynthesis; and (d) was also evident in two patients with recurrent glioblastoma multiforme. THC inhibited MMP-2 expression and cell invasion in cultured glioma cells. Manipulation of MMP-2 expression by RNA interference and cDNA overexpression experiments proved that down-regulation of this MMP plays a critical role in THC-mediated inhibition of cell invasion. Cannabinoid-induced inhibition of MMP-2 expression and cell invasion was prevented by blocking ceramide biosynthesis and by knocking-down the expression of the stress protein p8. As MMP-2 up-regulation is associated with high progression and poor prognosis of gliomas and many other tumors, MMP-2 down-regulation constitutes a new hallmark of cannabinoid antitumoral activity.” http://www.ncbi.nlm.nih.gov/pubmed/18339876

Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells.

“delta9-Tetrahydrocannabinol (THC), the major active component of marijuana, induced apoptosis in C6.9 glioma cells, as determined by DNA fragmentation and loss of plasma membrane asymmetry.” “Results thus show that THC-induced apoptosis in glioma C6.9 cells may rely on a CBI receptor-independent stimulation of sphingomyelin breakdown.” http://www.ncbi.nlm.nih.gov/pubmed/9771884

Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism.

“The effect of delta9-tetrahydrocannabinol (THC), the major psycho-active component of marijuana, in human prostate cancer cells PC-3 was investigated. THC caused apoptosis in a dose-dependent manner. Morphological and biochemical changes induced by THC in prostate PC-3 cells shared the characteristics of an apoptotic phenomenon.’ http://www.ncbi.nlm.nih.gov/pubmed/10570948

Cannabinoids and cell fate.

“Cannabinoids recently have been shown to control the cell survival/death decision. Thus, cannabinoids induce growth arrest or apoptosis in a number of transformed neural and non-neural cells in culture. In addition, cannabinoid administration induces regression of malignant gliomas in rodents by a mechanism that may involve sustained ceramide generation and extracellular signal-regulated kinase activation. In contrast, most of the experimental evidence indicates that cannabinoids may protect normal neurons from toxic insults, such as glutamatergic overstimulation, ischaemia, and oxidative damage. Regarding immune cells, low doses of cannabinoids may enhance proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis. The potential therapeutic applications of these findings are discussed.” http://www.ncbi.nlm.nih.gov/pubmed/12182964

Amphiregulin is a factor for resistance of glioma cells to cannabinoid-induced apoptosis.

“Gliomas, one of the most malignant forms of cancer, exhibit high resistance to conventional therapies.” “Delta9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the ability of these compounds to induce apoptosis of tumor cells.’ “Our findings therefore identify Amphirregulin as a factor for resistance of glioma cells to THC-induced apoptosis and contribute to unraveling the molecular bases underlying the emerging notion that targeted inhibition of the EGFR pathway can improve the efficacy of antitumoral therapies.” http://www.ncbi.nlm.nih.gov/pubmed/19229996

Potentiation of cannabinoid-induced cytotoxicity in Mantle Cell Lymphoma through modulation of ceramide metabolism

“Ceramide levels are elevated in Mantle Cell Lymphoma cells following treatment with cannabinoids.” “Furthermore, this is the first study were the cytotoxic effect of a cannabinoid is enhanced by modulation of ceramide metabolism.” http://www.ncbi.nlm.nih.gov/pubmed/19609004

Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma.

“We have earlier reported overexpression of the central and peripheral cannabinoid receptors CB1 and CB2 in mantle cell lymphoma,..” “Induction of apoptosis, as measured by FACS/Annexin V-FITC, contributed to the growth suppressive effect of Win-55,212-2. Our data suggest that cannabinoid receptors may be considered as potential therapeutic targets in MCL.” http://www.ncbi.nlm.nih.gov/pubmed/16337199

Cannabinoid Receptor-Mediated Apoptosis Induced by R(+)-Methanandamide and Win55,212-2 Is Associated with Ceramide Accumulation and p38 Activation in Mantle Cell Lymphoma

“We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB(1) and CB(2)).” “Taken together, these results suggest that concurrent ligation of CB(1) and CB(2) with either R(+)-MA or Win55 induces apoptosis via a sequence of events in MCL cells: accumulation of ceramide, phosphorylation of p38, depolarization of the mitochondrial membrane, and caspase activation. Although induction of apoptosis was observed in both MCL cell lines and primary MCL, normal B cells remained unaffected. The present data suggest that targeting CB(1)/CB(2) may have therapeutic potential for the treatment of mantle cell lymphoma.” http://www.ncbi.nlm.nih.gov/pubmed/16936228

Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: growth inhibition by receptor activation.

“Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL).” “Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2.” http://www.ncbi.nlm.nih.gov/pubmed/18546271

Arachidonylethanolamide induces apoptosis of human glioma cells through vanilloid receptor-1.

“The anti-tumor properties of cannabinoids have recently been evidenced, mainly with delta9-tetrahydrocannabinol (THC). “ “. We observed that AEA induced apoptosis in long-term and recently established glioma cell lines via aberrantly expressed vanilloid receptor-1 (VR1).” http://www.ncbi.nlm.nih.gov/pubmed/15453094

Cannabinoid receptor ligands as potential anticancer agents–high hopes for new therapies?

“In recent years, CB receptor ligands, including Delta(9)-tetrahydrocannabinol, have been proposed as potential anticancer agents.” http://www.ncbi.nlm.nih.gov/pubmed/19589225

Arachidonyl ethanolamide induces apoptosis of uterine cervix cancer cells via aberrantly expressed vanilloid receptor-1.

“Delta(9)-Tetrahydrocannabinol, the active agent of Cannabis sativa, exhibits well-documented antitumor properties,..” “Overall, these data suggest that the specific targeting of VR1 by endogenous cannabinoids or synthetic molecules offers attractive opportunities for the development of novel potent anticancer drugs.” http://www.ncbi.nlm.nih.gov/pubmed/15047233

Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma.

“Gene expression profiling has revealed that the gene coding for cannabinoid receptor 1 (CB1) is highly up-regulated in rhabdomyosarcoma biopsies bearing the typical chromosomal translocations PAX3/FKHR or PAX7/FKHR. Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis in diverse cancer cells such as glioma, breast cancer, and melanoma,..” “Our study shows that treatment with the cannabinoid receptor agonists HU210 and Delta(9)-tetrahydrocannabinol lowers the viability of translocation-positive rhabdomyosarcoma cells through the induction of apoptosis.” “These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma.” http://www.ncbi.nlm.nih.gov/pubmed/19509271

Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans.

“The most abundant malignant brain tumor in human is glioblastoma and patients with this type of tumor have a poor prognosis with high mortality.” “Cannabinoids (CBs) inhibit tumor growth by inducing apoptosis of tumor cells and impairing tumor angiogenesis.” “The abundant expression and distribution of CB2 receptors in glioblastoma and particularly endothelial cells of glioblastoma indicate that impaired tumor growth in presence of CB may be associated with CB2 activation. Selective CB2 agonists might become important targets attenuating vascular endothelial growth factor (VEGF) signalling and thereby diminishing neoangiogenesis and glioblastoma growth.” http://www.ncbi.nlm.nih.gov/pubmed/19480992

A comparative study on cannabidiol-induced apoptosis in murine thymocytes and EL-4 thymoma cells.

“It has been shown that leukemia and glioma cells are sensitive to cannabidiol (CBD)-induced apoptosis, whereas primary monocytes and glia cells are relatively insensitive. In the current study, the cellular events and sensitivity to CBD-induced apoptosis between murine thymocytes and EL-4 thymoma cells were compared. Cannabidiol markedly induced apoptosis in a time- and concentration-related manner in both cells.” http://www.ncbi.nlm.nih.gov/pubmed/18387516

The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration. at high concentration.

“The anticancer effect of Delta (9)-tetrahydrocannabinol (THC), the principal active component of cannabinoids has been demonstrated in various kinds of cancers. We therefore evaluate the antitumor effects of THC on cholangiocarcinoma cells.” “THC inhibited cell proliferation, migration and invasion, and induced cell apoptosis. THC also decreased actin polymerization and reduced tumor cell survival in anoikis assay. pMEK1/2 and pAkt demonstrated the lower extent than untreated cells. Consequently, THC is potentially used to retard cholangiocarcinoma cell growth and metastasis.” http://www.ncbi.nlm.nih.gov/pubmed/19916793

Antineoplastic and apoptotic effects of cannabinoids. N-acylethanolamines: protectors or killers?

“The proapoptotic and antineoplastic properties of cannabinoids with emphasis on effects of N-acylethanolamines were analyzed. Cannabinoids enhanced apoptotic and necrotic processes in many types of tumour cells and tissues. “ “The evidences in favour of both proapoptotic, pronecrotic and protective, antiapoptotic effects of cannabinoids and, especially N-acylethanolamines, are evaluated.” “The conclusion is made on promising of cannabinoids as potential anticancer agents.” http://www.ncbi.nlm.nih.gov/pubmed/18438336

Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway.

“We have shown that THC is a potent inducer of apoptosis, even at 1 x IC(50) (inhibitory concentration 50%) concentrations and as early as 6 hours after exposure to the drug. These effects were seen in leukemic cell lines…” “Additionally, THC did not appear to act synergistically with cytotoxic agents such as cisplatin.” “One of the most intriguing findings was that THC-induced cell death was preceded by significant changes in the expression of genes involved in the mitogen-activated protein kinase (MAPK) signal transduction pathways.” http://www.ncbi.nlm.nih.gov/pubmed/15454482

The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells.

“There is emerging evidence that cannabinoids, especially Delta(9)-tetrahydrocannabinol (THC), may represent novel anticancer agents, due to their ability to regulate signalling pathways critical for cell growth and survival. Here, we report that CB1 and CB2 cannabinoid receptors are expressed in human colorectal adenoma and carcinoma cells, and show for the first time that THC induces apoptosis in colorectal cancer cells.” “These data suggest an important role for CB1 receptors and BAD in the regulation of apoptosis in colorectal cancer cells. The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy.” http://www.ncbi.nlm.nih.gov/pubmed/17583570

Cannabinoid receptor agonists are mitochondrial inhibitors: a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death.:

“Time-lapse microscopy of human lung cancer (H460) cells showed that the endogenous cannabinoid anandamide (AEA), the phyto-cannabinoid Delta-9-tetrahydrocannabinol (THC) and a synthetic cannabinoid HU 210 all caused morphological changes characteristic of apoptosis.” “These data demonstrate that AEA, THC, and HU 210 are all able to cause changes in integrated mitochondrial function, directly, in the absence of cannabinoid receptors.” http://www.ncbi.nlm.nih.gov/pubmed/17931597

High concentrations of cannabinoids activate apoptosis in human U373MG glioma cells.:

“Cannabinoids bind to two G-protein-coupled receptors, CB1 and CB2, expressed by neurons and cells of the immune system, respectively. Glioma cells (astrocyte-derived brain tumor cells) express cannabinoid receptors, and numerous in vitro and in vivo studies performed in rodents have concluded that apoptosis could be induced by cannabinoids in these cells.” “We report here that U373MG human glioma cells are sensitive only to high concentrations of cannabinoids (>5 microg/ml for Delta(9)-THC). “ http://www.ncbi.nlm.nih.gov/pubmed/18615640

Cannabinoid receptor systems: therapeutic targets for tumour intervention.:

“Much of our understanding of the signalling mechanisms activated by cannabinoids is derived from studies of receptors expressed by tumour cells; hence, this review provides a succinct summary of the molecular pharmacology of cannabinoid receptors and their roles in tumour cell biology. Moreover, there is now a genuine expectation that the manipulation of cannabinoid receptor systems may have therapeutic potential for a diverse range of human diseases. Thus, this review also summarises the demonstrated antitumour actions of cannabinoids and indicates possible avenues for the future development of cannabinoids as antitumour agents.” http://www.ncbi.nlm.nih.gov/pubmed/14640910

 Cannabinoids as novel anti-inflammatory drugs:

“Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression” http://www.ncbi.nlm.nih.gov/pubmed/20191092

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells.:

“Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion.” “..CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness.” http://www.ncbi.nlm.nih.gov/pubmed/18025276

In vivo effects of cannabinoids on macromolecular biosynthesis in Lewis lung carcinomas.:

“Cannabinoids represent a novel class of drugs active in increasing the life span mice carrying Lewis lung tumors and decreasing primary tumor size.” http://www.ncbi.nlm.nih.gov/pubmed/616322

Cannabinoid receptor as a novel target for the treatment of prostate cancer.:

“Cannabinoids, the active components of Cannabis sativa Linnaeus (marijuana) and their derivatives have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects and tumor regression.” “Our results suggest that WIN-55,212-2 or other non-habit-forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer.” http://www.ncbi.nlm.nih.gov/pubmed/15753356

Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease.:

“In the current study, we examined whether ligation of CB2 receptors would lead to induction of apoptosis in tumors of immune origin and whether CB2 agonist could be used to treat such cancers. Exposure of murine tumors EL-4, LSA, and P815 to delta-9-tetrahydrocannabinol (THC) in vitro led to a significant reduction in cell viability and an increase in apoptosis. Exposure of EL-4 tumor cells to the synthetic cannabinoid HU-210 and the endogenous cannabinoid anandamide led to significant induction of apoptosis, whereas exposure to WIN55212 was not effective. Treatment of EL-4 tumor-bearing mice with THC in vivo led to a significant reduction in tumor load, increase in tumor-cell apoptosis, and increase in survival of tumor-bearing mice. Examination of a number of human leukemia and lymphoma cell lines, including Jurkat, Molt-4, and Sup-T1, revealed that they expressed CB2 receptors but not CB1. These human tumor cells were also susceptible to apoptosis induced by THC, HU-210, anandamide, and the CB2-selective agonist JWH-015. This effect was mediated at least in part through the CB2 receptors because pretreatment with the CB2 antagonist SR144528 partially reversed the THC-induced apoptosis. Culture of primary acute lymphoblastic leukemia cells with THC in vitro reduced cell viability and induced apoptosis. Together, the current data demonstrate that CB2 cannabinoid receptors expressed on malignancies of the immune system may serve as potential targets for the induction of apoptosis. Also, because CB2 agonists lack psychotropic effects, they may serve as novel anticancer agents to selectively target and kill tumors of immune origin.” http://www.ncbi.nlm.nih.gov/pubmed/12091357

Cannabinoids for cancer treatment: progress and promise.:

“Cannabinoids are a class of pharmacologic compounds that offer potential applications as antitumor drugs, based on the ability of some members of this class to limit inflammation, cell proliferation, and cell survival. In particular, emerging evidence suggests that agonists of cannabinoid receptors expressed by tumor cells may offer a novel strategy to treat cancer. Here, we review recent work that raises interest in the development and exploration of potent, nontoxic, and nonhabit forming cannabinoids for cancer therapy.” http://www.ncbi.nlm.nih.gov/pubmed/18199524

Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer:

“Cannabinoids have been reported to possess antitumorogenic activity. “ “We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue.” “Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. “ “In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system.” “These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis.” http://www.ncbi.nlm.nih.gov/pubmed/19887554

Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression:

“Cannabinoids have been shown to act as potent immunosuppressive and anti-inflammatory agents and have been shown to mediate beneficial effects in a wide range of immune-mediated diseases such as multiple sclerosis, diabetes, septic shock, rheumatoid arthritis, and allergic asthma. “ “Cannabinoids have been shown to be effective in the treatment of nausea and vomiting associated with cancer chemotherapy, anorexia and cachexia seen in HIV/AIDS patients, as well as neuropathic pain, and spasticity in multiple sclerosis…” “In 2002, studies from our laboratory suggested for the first time that targeting CB2 receptors on cancers of immune origin may constitute a novel approach to treat such malignancies (McKallip et al. 2002a). We first investigated the ability of cannabinoids to induce apoptosis in malignant cells of immune origin including lymphomas and leukemias (Lombard et al. 2005; McKallip et al. 2006, 2002a). It was demonstrated that human leukemia and lymphoma cell lines such as Jurkat cells and Molt-4 expressed CB2 receptors but express little or no significant levels of CB1. These cells were found to be susceptible to apoptosis induced by THC, HU-210, anandamide, and JWH-015 (McKallip et al. 2002a). In the same study, it was noted that apoptosis was also induced by THC and anandamide in murine tumor cells such as EL-4 and LSA. In vivo administration of 3 and 5 mg/kg bodyweight THC was also effective in killing EL-4 tumor cells that were injected into the peritoneal cavity, and upon THC treatment, 25% of the mice survived the tumor challenge. Primary lymphoblastic human leukemia cells were also tested for their susceptibility to THC-induced apoptosis, and the cells taken from two different donors showed increased apoptosis upon THC treatments at 5 μM or greater concentrations (McKallip et al. 2002a). Another observation by this study was that serum interfered with the effects of THC; therefore in serum-containing medium 10 μM or greater concentrations were needed to induce apoptosis; however, in serum-free conditions 3 μM or higher concentrations were sufficient to induce a significant increase in apoptosis. It is well established that THC induces apoptosis in Jurkat leukemia cell lines, and this occurs through three different mechanisms (Herrera et al. 2006; Jia et al. 2006; Lombard et al. 2005). The first mechanism was shown by Lombard et al. (2005), where the investigators examined the effect of THC on wild type as well as on FADD deficient, caspase 8 deficient, and caspase 9 deficient Jurkat cells. Their study demonstrated that THC-induced apoptosis in Jurkat cells occurred primarily through the intrinsic pathway including caspase 9 activation, and the release of cytochrome c into the cytosol. However, the degree of apoptosis in FADD deficient and caspase 8 deficient cells showed a partial decrease, when measured by TUNEL. THC treatment of the cells led to activation of caspases 2, 8, 9, and 10 in that order, and cleavage of Bid occurred 2 h after treatment. Overall, these studies demonstrated that THC-induced apoptosis occurred through cross-talk between the extrinsic and intrinsic pathways, with the intrinsic pathway playing the primary role (Lombard et al. 2005). The second proposed mechanism came from a research group in Spain, and in this particular study, the researchers investigated if ceramide accumulation is involved in THC-induced apoptosis in Jurkat cells (Herrera et al. 2006). They demonstrated that upon 2 μM THC treatment, ceramide levels were increased within the cell. They inhibited ceramide synthesis with a pharmacological inhibitor or transfected the cells with a dominant negative form of the enzyme that catalyzes ceramide production, and demonstrated that this led to decreased levels of apoptosis in the presence of THC. Apoptosis was mediated through loss of mitochondrial membrane potential, cytochrome c release, and caspase activation. When a pan caspase inhibitor was used, apoptosis was prevented but there still was loss of the membrane potential of the mitochondria. Therefore, this study showed that the first step in the apoptotic pathway was ceramide production, and that this led to loss of membrane potential, and caspase activation, respectively (Herrera et al. 2006). “..It was also demonstrated that THC-induced apoptosis in Jurkat T cells in a dose-dependent manner, and the use of CB1 and CB2 antagonists (SR141716 and SR144528, respectively) significantly decreased the amount of apoptosis induced by THC. “This paper shed more light on the mechanism of THC induced apoptosis in leukemic T cell lines, and demonstrated that ligation of CB1 and CB2 receptors by THC led to: (1) the disruption of a main cell survival pathway, (2) translocation of Bad into the mitochondria, and (3) apoptosis…” “In addition to the use of exogenous cannabinoids, in vivo manipulation of endocannabinoids may also offer novel treatment opportunities against cancer and autoimmune diseases.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005548/

Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria.:

“Plant-derived cannabinoids, including Delta9-tetrahydrocannabinol (THC), induce apoptosis in leukemic cells, although the precise mechanism remains unclear.” “Together, these data suggested that Raf-1/MEK/ERK/RSK-mediated Bad translocation played a critical role in THC-induced apoptosis in Jurkat cells.” http://www.ncbi.nlm.nih.gov/pubmed/16908594

Delta(9)-tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo.

‘..THC in vivo exhibited apoptosis upon in vitro culture. Together, these results suggest that in vivo exposure to THC can lead to significant suppression of the immune response by induction of apoptosis.” http://www.ncbi.nlm.nih.gov/pubmed/12130702

Cannabinoids and the immune system.:

“Further studies will define the precise structure and function of the putative immunocannabinoid system, the potential therapeutic usefulness of these drugs in chronic diseases such as acquired immune deficiency syndrome and multiple sclerosis, the effects of these agents on tumour growth and induction of apoptosis, and the potential anti-inflammatory and proinflammatory properties of cannabimimetic compounds. It is likely that the cannabinoid system, along with other neuroimmune systems, has a subtle but significant role in the regulation of immunity and that this role can eventually be exploited in the management of human disease.” http://www.ncbi.nlm.nih.gov/pubmed/11854771

Cannabidiol enhances the inhibitory effects of Δ9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival:

“We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with Delta(9)-THC. In the U251 and SF126 glioblastoma cell lines, Delta(9)-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. Our results suggest that the addition of cannabidiol to Delta(9)-THC may improve the overall effectiveness of Delta(9)-THC in the treatment of glioblastoma in cancer patients.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806496/

Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression.:

“In the current study, we examined the effects of the nonpsychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells. Exposure of leukemia cells to cannabidiol led to cannabinoid receptor 2 (CB2)-mediated reduction in cell viability and induction in apoptosis. Furthermore, cannabidiol treatment led to a significant decrease in tumor burden and an increase in apoptotic tumors in vivo.” “Furthermore, cannabidiol-induced apoptosis and reactive oxygen species (ROS) levels could be blocked by treatment with the ROS scavengers or the NAD(P)H oxidase inhibitors. Finally, cannabidiol exposure led to a decrease in the levels of p-p38 mitogen-activated protein kinase, which could be blocked by treatment with a CB2-selective antagonist or ROS scavenger. Together, the results from this study reveal that cannabidiol, acting through CB2 and regulation of Nox4 and p22(phox) expression, may be a novel and highly selective treatment for leukemia.” http://www.ncbi.nlm.nih.gov/pubmed/16754784

The Expression Level of CB1 and CB2 Receptors Determines Their Efficacy at Inducing Apoptosis in Astrocytomas:

“Cannabinoids represent unique compounds for treating tumors, including astrocytomas.” “..our study provides the first evidence for the differential activation of AKT, p38 and JNK by a highly efficacious cannabinoid agonist, CP-55,940, engaging either CB1 or CB2 receptors expressed at different levels. This shift in coupling precludes the use of cannabinoids at submicromolar concentrations as pro-apoptotic therapeutics, unless AKT is concomitantly inhibited. Our results also suggest that high concentrations of cannabinoids are preferable for efficacious treatment of malignant astrocytomas, because these concentrations bypass CB1 and CB2 receptor activation and induce apoptosis in all astrocytoma cell subpopulations.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806825/

Targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in Delta9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells.:

“Together, these data suggest that the intrinsic pathway plays a more critical role in THC-induced apoptosis while the extrinsic pathway may facilitate apoptosis via cross-talk with the intrinsic pathway.” http://www.ncbi.nlm.nih.gov/pubmed/15978942

 

The Use of Styrene Maleic Acid Nanomicelles Encapsulating the Synthetic Cannabinoid Analog WIN55,212-2 for the Treatment of Cancer.

“Synthetic cannabinoid WIN55,212-2 (WIN) has shown a promise as an anticancer agent…”
“SMA-WIN demonstrated characteristics theorized to improve in vivo drug biodistribution. Potent cytotoxicity was found against breast and prostate cancer cells in vitro, showing promise as a novel treatment against breast and prostate cancer.” http://www.ncbi.nlm.nih.gov/pubmed/26254360

 

 

The use of cannabinoids as anticancer agents.

“It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumour growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumour angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.” http://www.ncbi.nlm.nih.gov/pubmed/26071989

Phytocannabinoids for Cancer Therapeutics: Recent Updates and Future Prospects.

“Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in traditional and recreational medicine. The plant and constituents were central in the discovery of the endocannabinoid system, the most new target for drug discovery. The endocannabinoid system includes two G protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana’s psychoactive principle ∆(9)-tetrahydrocannabinol (∆9-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the proteins for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The endocannabinoid system has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer. Targeting the CB1 receptors become a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzyme by phytocannabinoids obtained from non-cannabis plant lacking psychotropic adverse reactions has garnered interest in drug discovery. These pCBs derived from plants beyond cannabis appear safe and effective with a wider access and availability. In recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development in cancer therapeutics. Several of them also target the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize, critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics.” http://www.ncbi.nlm.nih.gov/pubmed/26179998

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