Canna~Fangled Abstracts

The evolution of cannabinoid receptors in cancer

By February 7, 2023October 18th, 2023No Comments

 Author manuscript; available in PMC 2023 Sep 7.
Published in final edited form as:
WIREs Mech Dis. 2023 Jul-Aug; 15(4): e1602.

Published online 2023 Feb 7. doi: 10.1002/wsbm.1602

PMCID: PMC10484301
NIHMSID: NIHMS1921226
PMID: 36750231
Nakea M. Pennant and Cimona V. Hinton, PhD
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Abstract

Cannabis sativa (cannabis) has been used as a therapeutic treatment for centuries treating various diseases and disorders. However, racial propaganda led to the criminalization of cannabis in the 1930s preventing opportunities to explore marijuana in therapeutic development. The increase in recreational use of cannabis further grew concern about abuse, and lead to further restrictions and distribution of cannabis in the 1970s when it was declared to be a Schedule I drug in the USA. In the late 1990s in some states, legislation assisted in legalizing the use of cannabis for medical purposes under physician supervision. As it has been proven that cannabinoids and their receptors play an essential role in the regulation of the physiological and biological processes in our bodies. The endocannabinoid system (ECS) is the complex that regulates the cell-signaling system consisting of endogenous cannabinoids (endocannabinoids), cannabinoid receptors, and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The ECS along with phytocannabinoids and synthetic cannabinoids serves to be a beneficial therapeutic target in treating diseases as they play roles in cell homeostasis, cell motility, inflammation, pain-sensation, mood, and memory. Cannabinoids have been shown to inhibit proliferation, metastasis, and angiogenesis and even restore homeostasis in a variety of models of cancer in vitro and vivo. Cannabis and its receptors have evolved into a therapeutic treatment for cancers.

Keywords: Cannabinoids, antitumor effects, therapeutic, legislation

Visual Abstract:

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Derivatives of the cannabis sativa plant are highly regarded to ease symptoms caused by certain medical conditions. In cancer patients, cannabinoid-based medicines are used to treat chemotherapy-induced nausea, vomiting, and chronic pain. Cannabinoids and some cannabis-derived plant compounds bind to receptors CB1, CB2, and others, to elicit their effects in the body. Image Source: iStock by Getty Images; Creator: Charles Wollertz

1. INTRODUCTION

Cannabis sativa (cannabis) has been regarded for its therapeutic benefits since ancient times. The first recorded use of cannabis was over 12,000 years ago in Central Asia, modern-day Mongolia, and southern Siberia, for its use in religious practices, and various diseases and disorders,; migrating through China, Egypt, Greece, and later the Roman empire. Cannabis appeared in Western society in the 19th century through interactions between physicians, Muslim and Indian cultures pioneering the therapeutic use of cannabis in Europe to treat pain, arthritis, gout, gastrointestinal disorders, insomnia, blood clots, and parasites. Reaching South America in the 19th century and being carried north afterward, eventually reaching North America. Finally, it came to the United States at the beginning of the 20th century. It arrived in the southwest of the United States from Mexico, with immigrants fleeing the country during the Mexican Revolution of 1910–1911. The growing tension between the United State and Mexican immigrants during this time created many restrictions on the use of cannabis and made it illegal,. The Federal Bureau of Narcotics in the 1930s began to cultivate the Marihuana Tax Act to criminalize the unregistered and untaxed production and use of cannabis throughout the states. The head of the Federal Bureau of Narcotics, Harry J. Anslinger, spearheaded the act developing a campaign driven by racism. Anslinger often insinuated majority of marihuana users were minorities, especially African Americans. Anslinger alluded that marijuana use had adverse effects on these races inducing violence or causing insanity and would even encourage interracial relationships between white women and black men. Anslinger’s acquisitions were supported by the media and even films such as Reefer Madness in 1936. This propaganda assisted in Congress passing the Marihuana Tax Act of 1937 to nationally prohibit and regulated the production, distribution, and use of cannabis, and decimated all opportunities to explore marijuana in therapeutic development. Although it has been vastly used around the world for anti-nociception, anti-inflammation, anti-convulsant, and anti-emetic treatments,, it was not until the 1940s that, phytocannabinoids, Δ−9-tetrahydrocannabinol (THC) and cannabidiol (CBD) were extracted from the cannabis plant. In the 1960s, Mechoulam et al. synthesized THC and CBD to elucidate structures and stereochemistry– ushering in medical interest in cannabinoid research. However, the recreational use of cannabis (THC) became mainstream during this time, in the 1960s, as an increased use among adolescents and young adults grew causing a growing interest in research on its psychoactive effects,.

The findings from recreational use and research on its psychoactive effects negatively impacted the use and distribution of cannabis worldwide. These studies focused on the psychoactive properties of Δ9-THC in both animals (mice, monkeys, and dogs) and humans,. Which results indicate that Δ9-THC alters cognitive skills such as heightening feelings of anxiety, panic, or paranoia, alters auditory and visual perception, and impairs memory,. In humans, studies showed that cannabis-impaired users’ ability to repeat in forward and backward order a succession of digits, make a succession of repeated subtraction mentally, form concepts, read comprehensively, speak coherently, and transfer information from short to long-term memory storage. Additionally, studies showed that the short-term effects of cannabis use are dependent on the dose of the drug which affects levels of motivation, and specific intellectual task. Single moderate use can impair short-term memory. These studies were a concern for younger students since the number of younger users was steadily increasing, who would smoke during school hours, and how this would affect their learning and academics. Studies have reported an impaired sense of time causing delays and difficulties in oral communication. Moderate doses of cannabis caused difficulties with clarity in speech, impaired thought sequence, greater lag times in cues to speak, and irrelevant words and ideas. Low doses caused impairments to sensory and perceptual functions, inability to follow moving stimuli, and impairs motor coordination. These studies also concluded that cannabis use amongst younger users increased the number of automotive indecencies. Additionally, daily users face amotivational syndrome in which there’s an increased loss of apathy, loss of ambition, difficulty concentration, deterioration of performance at work or school, recurrent confusion, and impaired memory.

Additionally, the 1961 United Nations Single Convention on Narcotic Drugs and the declaration of cannabis being a Schedule I drug in the USA in 1970 further restricted the use and distribution of cannabis,. This created controversy over cannabis use and overshadowed the therapeutic benefits of cannabis in the form of CBD,. However, the Compassionate Use Act of 1996 made California the first state to legalize the use of cannabis for medical purposes under physician supervision. Since the Act of 1996 over 30 states including Washington, the District of Columbia., Guam, and Puerto Rico have legalized medical cannabis sales and distribution, and of those states, Alaska, California, Colorado, Maine, Massachusetts, Nevada, Oregon, and Washington including D.C., have legalized use of marijuana for adult recreation. Legislation such as this has assisted in reducing the barriers to cannabinoid research. As research continues to suggest the beneficial effects of cannabis in various pathological conditions and diseases, such as inflammation, epilepsy, glaucoma, neurodegenerative disorders, and cancer,, the controversial use of cannabis for research is beginning to fade.

This review will discuss the evolution of cannabis, cannabinoids, and their receptors as a therapeutic treatment for cancer, primarily breast and prostate.

2. ENDOCANNABINOID SYSTEM

Cannabinoids and their receptors play an essential role in the regulation of the physiological and biological processes in our bodies. The complex that regulates this cell-signaling system is called the endocannabinoid system (ECS) consisting of chemical signals and cellular receptors that are found in the brain, organs, connective tissues, glands, and immune cells. The ECS consists of endogenous cannabinoids (endocannabinoids), cannabinoid receptors, and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The first characterized endocannabinoids were arachidonoyl ethanolamide (anandamide) from the brain tissue and 2-arachidonoyl glycerol (2-AG) from peripheral tissue,,. Since then, more than 100 cannabinoids have been identified to regulate a variety of functions,.

The cannabinoid receptors are seven-transmembrane domain G protein-coupled receptors (GPCRs),. Cannabinoid receptors are coupled through the Gi/o family of proteins (are inhibitory proteins, with adenylyl cyclase and potassium channels as their main effectors), to signal transduction mechanisms that include inhibition of adenylyl cyclase, activation of mitogen-activated protein kinase, regulation of calcium and potassium channels, and other signal transduction pathways, as stated previously. The cannabinoids are divided into only two subtypes cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 regulates neurotransmission and various peripheral functions, whereas CB2 regulates immune and inflammatory pathways. Cannabinoid receptors are some of the most common GPCRs. Cannabinoid receptors also interact with other GPCRs and ion channels such as the activation of vanilloid receptor type 1 (TRPV1) channels, which mediates pain sensation and tissue injury-induced inflammatory thermal hyperalgesia; playing an essential role in chronic pain conditions, by anandamide or potassium channels, alpha7 nicotinic receptors, and 5-HT3 receptors. Endocannabinoids can also activate GPCRs in addition to CB1 and CB2 receptors such as GPR55 increases intracellular calcium in large dorsal root ganglion neuron, in which anandamide and 2-AG activate GPR55. Thus, the activation of CB1 or CB2 receptors assists with the regulation of cellular physiology, including synaptic function, gene transcription, and cell motility. They play an important factor in physiological processes such as pain sensation, mood, and memory.

2.1. CB1

CB1 is encoded by the gene CNR1 consisting of 472 amino acids in humans. CB1 is primarily localized in the nerve cells of the brain and the spinal cord. They are also present in organs like the spleen as well as the white blood cells, endocrine gland, and urinary, gastrointestinal, and reproductive tracts. It is most highly expressed by the axons and presynaptic termini of neurons in the amygdala, hippocampus, cortex, basal ganglia outflow tracts, and cerebellum,. Additionally, CB1 activation increases potassium and calcium ion channels interactions causing CB1 to regulate neurotransmitter release in a dose-dependent and pertussis toxin-sensitive manner. The main binding site of CB1 has an allosteric modulatory binding pocket. CB1 can exist as a homodimer, or as a heterodimer or hetero-oligomers complexed with other GPCRs.

2.2. CB2

CB2 is encoded by the gene CNR2, consisting of 360 amino acids in humans. It shares only 44% sequence homology with CB1 at the protein level. CB2 is found within the nervous system and is present in the spleen, gastrointestinal tract, and immune system. Unlike CB1, there are very few CB2 receptors in the brain. It can be expressed by some neurons, usually under certain pathological conditions such as nerve injury. CB2 is primarily expressed in peripheral tissues, found in the immune system and its associated structures,. CB2 receptors play an essential role in immune function, pain management, inflammation, cell migration, and cytokine release,.CB2 activation is associated with neuro-defense functions and ensures the maintenance of bone mass and the reduction of inflammation. CB2 agonists can slow neurodegenerative disorders such as Huntington’s and Alzheimer’s disease.

3. CLINICAL CANNABIS IN DISEASE

Cannabis has been used for therapeutic purposes for centuries. Currently, medical cannabis has proven to treat various diseases such as chronic pain,, cancer,, chemotherapy-induced nausea and vomiting, anorexia and weight loss,, irritable bowel syndrome, neurodegenerative disorders,, glaucoma,, traumatic brain injury, and various psychoses.

Many clinical trials have shown that synthetic cannabinoids and cannabis derivatives are effective in treating chronic pain related to multiple sclerosis (MS),. The CBD/THC buccal spray (Sativex) was found to be effective and well-tolerated in the treatment of symptoms of MS, spasticity, and neuropathic pain,. Sativex is the first cannabis-based medicine to undergo conventional clinical development and be approved as a prescription drug. Sativex has also been effective in improving sleep in patients with MS by decreasing the amount of sleep disturbances. Additionally, spasticity is typical in patients with other neurologic diseases and injuries such as stroke, cerebral palsy, and injury to the spinal cord. Cannabis was suggested as a treatment of muscle spasticity; in a mice study, control of spasticity in an MS model was found to be mediated by CB1, but not by CB2, cannabinoid receptors. In clinical trials, patients treated with THC had significant improvement in ratings of spasticity compared to placebo. Nabilone is another synthetic cannabinoid that has been proven to improve muscle spasms and nocturia,.

The CB1 receptor was shown to have a role in central appetite control, peripheral metabolism, and body weight regulation hence cannabis increases appetite and food consumption. CB1 receptor antagonist, Rimonabant, decreases appetite and food consumption. Rimonabant was administered to mice to suppress their intake of chocolate-flavored beverages over a 21-day treatment period. Rimonabant affects significant weight loss in obese patients. Additionally, in a study on obese vs lean rats conducted by Croci and Zarini, Rimonabant was found to be an inhibitor of sensory hypersensitivity associated with CFA-induced arthritis in obese rats, in which the inflammatory reaction is more severe than in lean rats. Rimonabant has also been shown to be effective in treating the combined cardiovascular risk factors of smoking and obesity. It also diminishes insulin resistance and reduces the prevalence of metabolic syndrome and improves type 2 diabetes.

Even though synthetic cannabinoids are proven to suppress appetite, cannabis has also been proven to assist with weight gain in anorexia-induced cancer and AIDS patients,. Cannabis-treated AIDS patients reported improved appetite, muscle pain, nausea, anxiety, nerve pain, depression, and paresthesia. Dronabinol, synthetic THC, is an approved treatment for nausea and vomiting in cancer and AIDS patients and is associated with consistent improvement in appetite. Dronabinol has also been used to treat patients with IBS with diarrhea. Additionally, Nabilone is also approved for the treatment of severe nausea and vomiting associated with cancer chemotherapy.

Cannabis can also assist patients with neurodegenerative disorders. A common therapy for patients with Parkinson’s disease (PD) is levodopa therapy which often causes the development of dyskinesias, and disabling motor complications. Rimonabant has also been shown to assist, in a dose-dependent matter, with the disabling motor complications in PD. Tourette syndrome causes multiple motor and vocal tics in diagnosed patients; THC is a beneficial treatment for advanced tics, as THC decreases and improves motor tics, vocal tics, and obsessive-compulsive behavior in Tourette syndrome patients. Patients with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder caused by a loss of motor neurons in the spinal cord, brain stem, and motor cortex, have used cannabis to treat their disorder. WIN 55,212–2, a cannabinoid receptor agonist and synthetic cannabinoid, has been proven to delay disease progression. Additionally, AM1241, a CB2-selective agonist, is effective at decreasing ALS progression, delaying motor impairment when treated during tremors, and prolonging survival in mice. CBD has been shown to improve the anti-convulsant effects of drugs in major seizures and reduces their effects in minor seizures making CBD an ideal treatment for patients with epilepsy.

Cannabis use for psychosis treatment can be controversial, especially when treating schizophrenia. Studies have shown that anandamide levels are enhanced in first-episode schizophrenic patients and that THC downregulates anandamide signaling. Also, personality changes generated by schizophrenia progression are equivalent to psychopathological occurrence due to cannabis intoxication. A study showed that long-term cannabis use in first-episode schizophrenic patients was younger at disease onset and had more often paranoid schizophrenia compared to those without cannabis usage. However, CBD causes antipsychotic effects and has been used to treat schizophrenia. In bipolar disorder, patients commonly use cannabis to suppress symptoms of mania and depression. Additionally, studies have shown the repetitive use of Nabilone reduces anxiety and has assisted posttraumatic stress disorder patients with nightmare,.

THC and other cannabinoids have shown promise in treating ocular hypertension which is a vital risk factor for glaucoma. THC Nabilone and cannabinol (CBN) have been shown to lower intraocular pressure in rabbits. Whereas in cats when applied topically whole cannabis extract, THC, and other phytocannabinoids reduce lower intraocular pressure. Smoking cannabis has also been proven to reduce intraocular pressure.

3.1. Effects of Cannabis on Cancers

Cannabinoids have been studied in various cancer types such as brain, breast, lung, and prostate cancers,. Cannabinoids are known to be suppressors of angiogenesis and tumor invasion affecting the growth, migration, and invasion of some tumors,.

In breast cancer, CB2 receptors are overexpressed in which more than 90% of HER-2 positive tumors have this overexpressed cannabinoid receptor. Which correlates with a poor prognosis. CB2 receptors are also overexpressed in major recurrence-free survival in patients with both estrogen-receptor-positive and negative mammary tumors. AEA, 2-AG, and other endocannabinoids can have the ability to inhibit the proliferation of breast cancer cells, via CB1 receptors. Several phytocannabinoids including Δ9 -THC and CBD and synthetic cannabinoids such as WIN-55,212–2 and JWH-133 are also anti-proliferative in a cannabinoid receptor-dependent manner. THC, through activation of CB2, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis. Additionally, cannabinoids in conjunction with other anti-tumor drugs such as Rimonabant, Tamoxifen, and Cisplatin pose as a possible treatment for breast cancer. Rimonabant can inhibit human breast cancer cell proliferation through a lipid raft-mediated mechanism.

In prostate cancer, CB1 and CB2 receptors are higher in comparison to normal prostatic tissue. Also, the CB1 receptor is overexpressed in the Gleason score, and metastasis incidence serves as a negative marker for the prostate cancer prognosis. Anandamide is an anti-proliferative that inhibits the proliferation of prostate cancer cells, LNCaP, DU-145, and PC3, and primary cultures of prostate carcinoma via CB1 receptors. However, the proliferative activity of CBD and Δ9-THC does not involve cannabinoid receptors. Endocannabinoids also can decrease the invasion of prostate cancer cells. 2-AG is hypothesized to be a potential inhibitor of androgen prostate tumor invasion via the CB1. The increase of endogenous 2-AG levels via MAGL inhibition has anti-invasive effects on prostate cancer. MAGL inhibitors lower the invasive capacity of prostate cancer which can be partially reversed by the blockage of CB1 receptors. The disruption of MAGL activity also affects the epithelial growth factor receptor expression, reducing the proliferation induced by the epithelial growth factor. Additionally, cannabinoid-induced apoptosis of LNCaP can progress through the continuous activation of ERK1/2 leading to Gl cell cycle arrest.

3.2. Controversy (pro/anti-tumorigenic)

The usage of cannabinoids is promising as a treatment for cancers as it can induce apoptosis and inhibit cancer-promoting mechanisms, such as angiogenesis, proliferation, and invasion. However, there is some controversy, as cannabinoids can be both pro/anti-tumorigenic.

Cannabinoids have been proven to be pro-tumorigenic, in which there is a correlation between the increased presence of endocannabinoids and their receptors and an increase in cancer. Often correlating with tumor aggressiveness. Anandamide and 2-AG are over-expressed in various tumor types such as glioblastoma multiforme (GBM), meningioma, pituitary adenoma, prostate and colon carcinoma, and endometrial sarcoma. Endocannabinoid levels have been associated with increased disease progression in a mouse model of metastatic melanoma as well as in human samples. CB1 receptors are upregulated in Hodgkin lymphoma cells and chemically induced cellular hepatocarcinoma. CB1 receptor levels are also increased in epithelial ovarian tumors and stage IV colorectal cancer and have been proposed to be a factor of bad prognosis. The CB2 receptor is over-expressed in breast cancer and gliomas.

Additionally, cannabinoids are involved in responses and alleviating inflammation, which have critical roles in cancer progression. They modulate the immune response in both cancerous and non-cancerous diseases. Cannabinoid receptors mediate the immune system through the production of anti-inflammatory cytokines/chemokines as well as the suppression of pro-inflammatory mediators in immune-associated diseases. Which is important in determining cancer cells’ growth, migration, and invasion. AEA induces the downregulation of inflammasome components’ expression and decreases IL-1β production which facilitates tumor cell progression. Endocannabinoids and the ECS affect the leukocytes in the tumor microenvironment (TME), which are responsible for regulating tumor progression and may assist in determining the vitally of cancer cells.

Although, some data suggest that the endocannabinoid system may play a pro-tumorigenic role; there is evidence that endocannabinoids and their derivatives do have the ability to inhibit and participate in anti-tumorigenic processes. The next section will go further into detail about the anti-tumorigenic effects of cannabinoids.

4. CANNABINOID RECEPTORS INHIBIT CANCER

Endocannabinoids as an anti-tumorigenic therapeutic have been vastly studied, and activation of the cannabinoid receptors has been shown to impair cancer development,. Cannabinoids, phytocannabinoids (THC, CBD), endocannabinoids (2-arachidonoylglycerol, anandamide), and even synthetic cannabinoids (JWH-133, WIN-55,212–2), have been shown to inhibit proliferation, metastasis, and angiogenesis and even restore homeostasis in a variety of models of cancer (in vitro and vivo),. Cannabinoids stimulate anti-proliferative effects by inducing apoptosis and autophagy,.

Stimulation of CBRs in vitro and vivo can lead to autophagy-induced cell death involving various endoplasmic reticulum (ER) stress-related signaling pathways and proteins,. ER stress-related protein p8, which often is upregulated upon cannabinoid treatment, activation causes inhibition of, pro-survival, protein kinase B (Akt) via, ER stress-related protein, pseudo-kinase tribbles homolog 3 (TRIB3)–. This then leads to inhibition of the mammalian target of rapamycin complex 1 (mTORC1) essentially causing autophagy-mediated cell death–. This endoplasmic reticulum (ER) stress-related signaling pathways and proteins play a role in hepatocellular carcinoma autophagy in vitro and in vivo. Stress-induced by cannabinoids can lead to an activation of AMP-activated protein kinase and calcium/calmodulin-dependent protein kinase 2 causing autophagy-mediated cell death in hepatocellular carcinoma,. Additionally, THC and the CB2 receptor agonist JWH-015 are used to stimulate autophagy in hepatocellular carcinoma. This process has also been seen in breast carcinoma and melanoma in which the activation of CBRs depends on the downregulation of the Akt. The inhibition of Akt leads to the activation of cyclin-dependent kinase inhibitory proteins p21 and p27, causing phosphorylation of the retinoblastoma protein and eventually cell cycle arrest and apoptosis,.

The downregulation of Akt signaling can also cause apoptosis in glioma. This leads to a reduction in phosphorylation of Bcl-2-associated death promoter (BAD), a proapoptotic Bcl-2 family member, and the activation of transient receptor potential vanilloid 2 receptors (TRPV2),. Apoptosis of tumor cells and inhibition of their proliferation and metastasis via the activation of CBRs can also occur through various pathways via regulation of RAS/MAPK and PI3K–AKT, TNFα-induced ceramide synthesis, COX-2-dependent cell death, and many other mechanisms.

Additionally, studies have shown cannabinoids can induce apoptosis of glioma cells via CB1R and CB2R-dependent de novo synthesis of the sphingolipid ceramide which has pro-apoptotic properties. Vascular endothelial growth factor (VEGF)-induced cancer cell angiogenesis can be down-regulated by the activation of CBRs in skin carcinomas, gliomas, and thyroid carcinoma. Additionally, CB1R and/or CB2R agonists can lead to inhibition of adhesion and local and distant invasion in induced and spontaneous metastatic in vitro and in vivo models of glioma, breast, lung, and cervical cancer. This evidence further supports the notion that cannabinoid receptors can be used as an anti-tumorigenic therapeutic.

4.1. Heteromerization with other GPCRs

Cannabinoid receptors are GPCRs; GPCRs can form homodimers, heterodimers, and higher-order oligomers with both GPCRs and non-GPCRs. There is a growing interest in heteromers with cannabinoid receptors as a therapeutic treatment in cancers,. Heteromers are implicated in many disease-related processes in which heteromerization of receptors can alter ligand binding and affinity causing inhibition or activation of ligands,. Thus making it a promising anti-tumorigenic therapeutic treatment.

In prostate and breast cancer cells, CB2R can heterodimerize with GPCR C-X-C chemokine receptor type 4 (CXCR4),. CXCR4 is associated with metastatic mechanisms as it can regulate proliferation and migration causing local and distant metastatic invasion,. CB2 and CXCR4 agonist inhibits invasion and migration this is caused by the reduction of CXCR4 mediated ERK1/2 dependent migration,. This heterodimerization has also been linked to the inhibition of Gα13/RhoA signaling in prostate cancer cancers in which RHOA and Gα13 proteins decrease once the heteromer is formed,. The decrease of RHOA and Gα13 causes the cytoskeleton to diminish affecting cell migration,.

In breast cancer, CB2R can heterodimerize with tyrosine kinase receptor (TKR) human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) causing a collaborative anti-tumorigenic affect,. CB2R regulates HER2 signaling when there is no exogenous cannabinoids. However, both CB2R and HER2 are overexpressed in breast cancer correlating with poor prognostic biomarkers and aggressive high-grade tumors,. Additionally, they both affect protumorigenic mechanisms such as cellular proliferation, development, differentiation, and angiogenesis. Thus, making the CB2R-HER2 heteromer a potential therapeutic anti-cancer treatment,. It has been shown that the CB2R-HER2 heteromer via THC can promote an anti-tumorigenic response by inactivating and degrading HER2. In which THC binds specifically to CB2R,.

Additionally, the CB2R- GPR55 heteromer is involved and overexpressed in various cancer types such as breast cancer, bone, and hematopoietic cells,. When the heteromer is activated, it is anti-tumorigenic reducing tumor growth,. Also, CB1R can form heteromers with GPR55 in immortalized human embryonic kidney cells, HEK-293 cells. Furthermore, Cannabinoid heterodimerization can provide anti-tumorigenic effects on the protumorigenic mechanism and can be a potential anti-tumorigenic therapeutic treatment.

4.2. Prevention in Cancer

Cannabinoids have anti-tumor effects by decreasing the viability, proliferation, adhesion, and migration of various cancer cells, making them an ideal cancer treatment. Medical cannabis specifically targets tumor cells but has low potency for non-tumor cells compared to traditional chemotherapy which cytotoxicity affects tumor and non-tumor cells a like.

In breast cancer, THC inhibits overall cell growth and proliferation,. THC inhibits estradiol-induced cell proliferation by inhibiting estrogen receptor α activation. THC inhibits breast cancer proliferation at the G2/M phase via CB2 due to the downregulation of cell division control (Cdc2) which in turn induces apoptosis,. In vivo, THC reduces ErbB2-driven metastatic breast cancer growth and reduces metastasis to the lung. THC inhibits the heterodimerizations of HER2 and CB2 preventing the tumorigenesis of breast cancer in vitro and vivo,. Furthermore, in vivo THC significantly reduces tumor growth and decreased the expression of the HER2 protein,.

Several studies have examined the effects of CBD in vitro and in vivo in breast cancer. CBD induces apoptosis and autophagy via reactive oxygen species (ROS) production causing endoplasmic reticulum stress apoptosis in select breast cancer cells. CBD inhibits epidermal growth factor (EGF)-induced proliferation, migration, and invasion of breast cancer cells. CBD significantly reduces migration, invasion, and expression of malignant markers as well as promotes the recovery of cell contacts in 6D, the invasive mesenchymal-like phenotype in MCF-7, breast cancer cells. CBD also increases sensitivity to anti-cancer drugs doxorubicin and cisplatin in 6D cells by downregulating the expression of resistance proteins. CBD reduces advanced-stage breast cancer metastasis via the downregulation of the Inhibitor of DNA binding protein 1 (Id1), a transcriptional factor and marker for breast cancer cell metastasis to the lung. CBD also reduces the proliferation and invasion of breast cancer cells by reducing the expression of Id-1,.

Several studies have reported that synthetic cannabinoids such as WIN55,212, JWH-133, and JWH-015 can reduce the size of prostate cancer cell-derived tumors. In prostate cancer, WIN55,212–2 prevents proliferation and survival of LNCaP cells via AMP-activated protein kinase (AMPK) signaling inhibition,. Several in vivo studies have shown that WIN55,212-2 inhibits tumor growth in mice,In which has reduced the size of PC3-, DU145-, and LNCaP-induced tumors by 46–69%,,.

Synthetic cannabinoids also play a pivotal role in preventing prostate cancer metastasis in the tumor microenvironment. WIN 55–212-2 can selectively impair cell survival in prostate cancer cells while regulating prostate-associated fibroblast phenotypes in vitro. WIN55,212–2 significantly reduces cell proliferation, invasion, and migration, as well as induces G0/G1 cell cycle arrest apoptosis, in a dose-dependent manner in cultured prostate cancer cells. All of which are mediated via cell cycle regulators p27, Cdk4, and pRb. Additionally, PM49, a very potent derivative of the synthetic cannabinoid quinone, almost completely blocks the growth of LNCaP tumors and inhibits 40% of PC3 tumor growth in which PM49 is androgen sensitive.

Endocannabinoids have also inhibited the growth of PC3 prostate cancer cells via inhibiting adenylate cyclase and protein kinase A activity, arresting the cell cycle via the induction of p27 and downregulation of the EGF receptor,. Endocannabinoids have inhibited the growth and induces apoptosis in primary prostate tumors via activation of the ERK signaling pathway,.

Phytocannabinoids THC and CBD have been shown to reduce prostate cancer cell viability by inducing apoptosis. THC induces apoptosis in a dose-dependent and cannabinoid receptor-independent manner in prostate cancer cells.CBD inhibits prostate cancer cell growth via the induction of intrinsic pathways of apoptosis, cell cycle arrest at the G1-S phase, and activation of p53 and elevated ROS levels. CBD when used in combination with anti-cancer drugs, Docetaxel and Bicalutamide, can effectively inhibit tumor growth in vivo and vitro.

Conclusion

Cannabinoids employ anti-tumorigenic effects on various tumor types. Cannabinoids have been proven to be tumor suppressors affecting proliferation, migration, and invasion inducing apoptosis and autophagy. Cannabinoids also regulate vital processes that are essential physiologically and biologically such as cell homeostasis, cell motility, inflammation, pain-sensation, mood, and memory. To date, there are very few clinical studies on cannabinoids and these studies focus on alleviating cancer-related pain, nausea, and anorexia through the use of cannabinoids,,. However, the evidence from in vitro and in vivo studies highlights the anti-cancer characteristics of endocannabinoids, phytocannabinoids, and synthetic cannabinoids in cancer making cannabinoids a promising therapeutic treatment for cancer patients. More research and clinical studies would further assist in developing cannabinoids as a common treatment choice. More studies should be done to investigate the use of cannabinoids as a combination treatment with chemo and radiotherapy in which cannabinoids may decrease the amount and dose of chemotherapy drugs or radiation needed to achieve the same anti-cancer effect and even decrease potential side-effects of chemo and radiotherapy.

Additionally, there needs to be further investigation and development on cannabinoids’ mechanistic approach to tumorigenesis and metastasis. Issues such as which cancer patient populations would be most responsive to cannabinoid therapeutics should be addressed considering the anti-tumorigenic effects of cannabinoids are dependent on the cancer type, dosage, and even signaling mechanisms. Thus, it is vital to understand the signaling mechanism of cannabinoid receptors and their effects on various tumor types which may lead to a more targeted anti-cancer approach. Furthermore, investigating the cellular response to cannabinoids in different cancer types might provide a better understanding of the tumor microenvironment and the immune system in turn reducing inflammation, inhibiting tumor cell growth, inducing apoptosis, and even causing autophagy in cancer cells.

Furthermore, legislation on the use of medical cannabis is still very strict and controversial. The classification of cannabis as a Schedule I drug set by the United States Drug Enforcement Administration places stringent conditions on researchers and makes scientific research of cannabinoids difficult on a large scale. However, further research and the current use of medical cannabis as a treatment for the disease may improve legislation by loosening restrictions and making it more accessible in states where it is illegal. This can also be done if legislation and federal officials considered establishing more laws that allowed more scientific studies on cannabis.

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Endocannabinoids are naturally occurring endogenous lipids that interact with cannabinoid receptors. All mammals produce cannabinoids naturally, and they are central to creating therapeutic functions in the body. The endocannabinoid/cannabinoid receptor signaling cascade leads to various physiological processes. Phytocannabinoids also naturally occurring cannabinoids found in a variety of plants including rhododendron, licorice, liverwort, echinacea, and cannabis sativa. Once consumed, phytocannabinoids regulate biological homeostasis in the body through binding with cannabinoid receptors. Source: iStock by Getty Images; Creator: About time

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Plant-derived and synthetic cannabis, and cannabis metabolites, have retained a centuries-long interest in relief for various diseases and conditions. Image Source: iStock by Getty Images; Creator: ST.art

Schedule I Drug, Medical Cannabis Controversial Use:

The legalization and use of medical cannabis, derived from the subspecies of the flowering plant genus cannabis, has been controversial throughout the world, especially in the United States (U.S.). The U.S. Drug Enforcement Administration (DEA) classified the cannabis plant and its psychoactive cannabinoids as Schedule I Drug which are substances, generally, that have no medical value and a high potential for abuse,. However, cannabis is recommended by physicians to their patients, but not legally prescribed, to alleviate medical symptoms and conditions associated with chronic disease and pain, and the type of cannabis and dosages are dependent on state regulations. Prescribing cannabis would constitute aiding and abetting the purchase of marijuana, which could result in withdrawal of DEA licensure and even prison time as cannabis is illegal federally. Additionally, cannabis’ Schedule I classification limits and restricts the conduction of research because any cultivation, clinical testing, or cannabis research must attain the approval of the federal government. Approval is very difficult to attain as there is only one approved supplier, the National Center for Natural Products Research at the University of Mississippi, of marijuana for research purposes in the United States. However, relisting cannabis as a Schedule II controlled substance will assist in more extensive research and evidence on the medical benefits of cannabis. Schedule II drugs are still considered highly addictive as a result prescriptions for these medications are limited in the amount that can be prescribed. However, Schedule II drugs are deemed to have medical value.

Acknowledgments

We thank Dr. Balakrishna Lokeshwar of the Georgia Cancer Center at Augusta University, and Dr. Daqing Wu of the CCRTD at Clark Atlanta University for invaluable expertise and guidance.

Funding Information

We thank the following programs for financial support of our research (i) the State of Georgia for the Clark Atlanta University/Georgia Cancer Center at Augusta University Collaboration Pilot Project; and (ii) the Fine Fettle, Inc. for their donor gift, the Research Excellence Award.

Footnotes

Conflict of Interest

The authors have declared no conflicts of interest for this article.

 

Contributor Information

Nakea M. Pennant, Clark Atlanta University.

Cimona V. Hinton, Clark Atlanta University.

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