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

Abstract

Prostate cancer is the most common malignancy among men of all races and is one of the leading causes of cancer death in this population (Schroder, 2010). Although significant advances have been made in the early screening and treatment of prostate cancer by various pharmacological, surgical and radiotherapy approaches during the past decade, the traditional approach of radical treatment may often lead to severe adverse consequences and decreased quality of life.

The palliative effects of Cannabis sativa (marijuana) and its putative main active ingredient, the Δ⁹-tetrahydrocannabinol (THC), which include inhibition of nausea and emesis associated with chemo- or radiotherapy, appetite stimulation, pain relief, mood elevation and relief from insomnia in cancer patients, have been well recognized for centuries (Pacher et al., 2006). Synthetic THC (Marinol, Dronabinol) and its derivative nabilone (Cesamet), as well as plant-derived extracts containing controlled amounts of THC and other plant-derived cannabinoids (Sativex), have been approved in several countries to control nausea in cancer patients undergoing chemotherapy, to stimulate appetite and/or to attenuate cancer-related pain (Pacher et al., 2006; Velasco et al., 2012).

In addition to the therapeutic effects outlined above, THC, synthetic cannabinoid ligands and endocannabinoids or endocannabinoid-like substances have all been shown to induce cell death and to inhibit proliferation and/or migration of several murine and/or human cancer cell lines, as well as inhibiting the growth of certain types of tumours or tumour cell xenografts in vivo (Guindon and Hohmann, 2011; Velasco et al., 2012), including prostate cancer (Diaz-Laviada, 2011). Accumulating evidence indicates that a functional endocannabinoid system exists in normal prostate tissue, which is dysregulated in prostate cancer (Diaz-Laviada, 2011). Furthermore, overexpression of several components of the endocannabinoid system appears to correlate with the prostate cancer grade and progression (Diaz-Laviada, 2011).

Because the clinical use of THC is limited by adverse psychoactive effects, numerous non-psychoactive constituents of C. sativa, particularly cannabidiol, have been extensively investigated in preclinical models of inflammation (Izzo et al., 2009; Russo, 2011) and cancer (Guindon and Hohmann, 2011; Massi et al., 2012) recently. Most of these preclinical studies emphasize the extensive therapeutic potential of cannabidiol in various types of inflammatory diseases (Izzo et al., 2009) and cancers (Massi et al., 2012).

In this very interesting paper, the authors (De Petrocellis et al., 2012) describe the results of a very comprehensive study carried out with non-psychoactive cannabinoids on prostate carcinoma cells. The authors first screened 12 plant cannabinoids, including THC, and cannabinoid-enriched extracts from the strains of Cannabis selected to produce most of the corresponding compounds. They have done so in four different androgen receptor-dependent and -independent cell lines, and used normal culturing conditions, as well as conditions of serum deprivation. They presented novel data that plant-derived cannabinoids, and cannabidiol in particular, are potent inhibitor of prostate carcinoma viability under conditions of serum deprivation; whereas the extracts are more efficacious under normal culturing conditions. Next, the authors investigated if one of the most potent cannabinoid-enriched extracts in vitro was also efficacious in vivo, following systemic administration, in xenograft models obtained by using two of the four cell lines used in vitro. They reported that the extract is also active in vivo, either alone or when administered with the anti-androgen bicalutamide (Casodex) or a potent anti-mitotic chemotherapeutic drug docetaxel (Taxotere), which are often used to treat prostate cancer. Finally, the authors investigated, in all four prostate carcinoma cell lines, the cellular and molecular mechanism of action of cannabidiol and other two pure cannabinoids. They reported that these compounds act mostly by inducing apoptosis via activation of intracellular intrinsic pathways, which only partially involves antagonism of transient receptor potential cation channel subfamily M member 8 (TRPM8) and/or androgen receptor down-regulation (and only in certain cancer cell lines). This pro-apoptotic effect in cancer cells was independent of cannabinoid receptors or other TRP channels and, in the case of cannabidiol, was accompanied by intracellular calcium elevation and/or reactive oxygen species formation, depending on the cell line. Finally, the authors also showed that cannabidiol is more efficacious in inducing apoptosis in LNCaP cells that were partially differentiated into neuroendocrine-like cells, an in vitro model of invasive and untreatable prostate carcinoma.

Taken together, the results in this paper represent a considerable experimental effort and provide a wealth of important information on how plant-derived, non-psychoactive, cannabinoids can induce apoptosis in prostate carcinoma cells through a variety of mechanisms. The in vivo data, obtained in xenograft models, suggest that these compounds, and cannabidiol in particular, should be further tested against this type of cancer. This finding, coupled with recent evidence suggesting that cannabidiol inhibits angiogenesis (Solinas et al., 2012) and various key pro-inflammatory pathways (e.g. NF-κB, COX-2 and inducible NOS) (Mukhopadhyay et al., 2011) implicated in growth and progression of various malignancies, and also attenuates the tissue injury caused by a widely used chemotherapeutic drug cisplatin (Pan et al., 2009), is particularly encouraging from a therapeutic point of view.

The results described in this paper also supplement previous evidence that THC can counteract prostate carcinoma in vitro and in vivo via activation of cannabinoid CB₁ and CB₂ receptors (Sarfaraz et al., 2005; 2008) and are therefore important in view of the recent use and marketing of Sativex (1:1, THC : cannabidiol preparation) for the treatment of neuropathic pain and spasticity in patients with multiple sclerosis, and coupled with previous reports (Sarfaraz et al., 2005; 2008; Diaz-Laviada, 2011) provide a strong rationale for clinical testing of cannabidiol and Sativex (the toxicology of which have been widely investigated in humans) (Izzo et al., 2009) against prostate carcinoma.

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