http://www.ncbi.nlm.nih.gov/pubmed/11269508: Cannabinoids, the active components of Cannabis sativa (marijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids in recent years. 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 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 antiproliferation. Regarding the immune system, low doses of cannabinoids may enhance cell proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis. 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. Ongoing investigation is in search for cannabinoid-based therapeutic strategies devoid of nondesired psychotropic effects.
http://www.ncbi.nlm.nih.gov/pubmed/19690545: We have previously shown that cannabinoids induce growth inhibition and apoptosis in prostate cancer PC-3 cells, which express high levels of cannabinoid receptor types 1 and 2 (CB(1) and CB(2)). In this study, we investigated the role of CB(2) receptor in the anti-proliferative action of cannabinoids and the signal transduction triggered by receptor ligation. METHODS: The human prostate cancer cell lines, namely PC-3, DU-145 and LNCaP, were used for this study. Cell proliferation was measured using MTT proliferation assay, [(3)H]-thymidine incorporation assay and cell-cycle study by flow cytometry. Ceramide quantification was performed using the DAG kinase method. The CB(2) receptor was silenced with specific small interfering RNA, and was blocked pharmacologically with SR 144528. In vivo studies were conducted by the induction of prostate xenograft tumours in nude mice. RESULTS: We found that the anandamide analogue, R(+)-Methanandamide (MET), as well as JWH-015, a synthetic CB(2) agonist, exerted anti-proliferative effects in PC-3 cells. R(+)-Methanandamide- and JWH-015-induced cell death was rescued by treatment with the CB(2) receptor antagonist, SR 144528. Downregulation of CB(2) expression reversed the effects of JWH-015, confirming the involvement of CB(2) in the pro-apoptotic effect of cannabinoids. Further analysing the mechanism of JWH-015-induced cell growth inhibition, we found that JWH-015 triggered a de novo synthesis of ceramide, which was involved in cannabinoid-induced cell death, insofar as blocking ceramide synthesis with Fumonisin B1 reduced cell death. Signalling pathways activated by JWH-015 included JNK (c-Jun N-terminal kinase) activation and Akt inhibition. In vivo treatment with JWH-015 caused a significant reduction in tumour growth in mice. CONCLUSIONS: This study defines the involvement of CB(2)-mediated signalling in the in vivo and in vitro growth inhibition of prostate cancer cells and suggests that CB(2) agonists have potential therapeutic interest and deserve to be explored in the management of prostate cancer.
http://www.ncbi.nlm.nih.gov/pubmed/10570948: 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. First, loss of plasma membrane asymmetry determined by fluorescent anexin V binding. Second, presence of apoptotic bodies and nuclear fragmentation observed by DNA staining with 4',6-diamino-2-phenylindole (DAPI). Third, presence of typical 'ladder-patterned' DNA fragmentation. Central cannabinoid receptor expression was observed in PC-3 cells by immunofluorescence studies. However, several results indicated that the apoptotic effect was cannabinoid receptor-independent, such as lack of an effect of the potent cannabinoid agonist WIN 55,212-2, inability of cannabinoid antagonist AM 251 to prevent cellular death caused by THC and absence of an effect of pertussis toxin pre-treatment.
http://www.ncbi.nlm.nih.gov/pubmed/15753356: 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. Here we show that expression levels of both cannabinoid receptors, CB1 and CB2, are significantly higher in CA-human papillomavirus-10 (virally transformed cells derived from adenocarcinoma of human prostate tissue), and other human prostate cells LNCaP, DUI45, PC3, and CWR22Rnu1 than in human prostate epithelial and PZ-HPV-7 (virally transformed cells derived from normal human prostate tissue) cells. WIN-55,212-2 (mixed CB1/CB2 agonist) treatment with androgen-responsive LNCaP cells resulted in a dose- (1-10 micromol/L) and time-dependent (24-48 hours) inhibition of cell growth, blocking of CB1 and CB2 receptors by their antagonists SR141716 (CB1) and SR144528 (CB2) significantly prevented this effect. Extending this observation, we found that WIN-55,212-2 treatment with LNCaP resulted in a dose- (1-10 micromol/L) and time-dependent (24-72 hours) induction of apoptosis (a), decrease in protein and mRNA expression of androgen receptor (b), decrease in intracellular protein and mRNA expression of prostate-specific antigen (c), decrease in secreted prostate-specific antigen levels (d), and decrease in protein expression of proliferation cell nuclear antigen and vascular endothelial growth factor (e). 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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339795: Cannabis sativa and its main active component delta-9-THC have long been used for numerous purposes throughout history including medicinal, textile, and recreational. Since its legal banning in the United States in 1937, it has become an issue of taboo and controversy, frowned upon for its recreational uses and psychotropic effects. Nonetheless, the endocannabinoid signaling system has recently been the focus of medical research and considered a potential therapeutic target[15–17] since the late 1980s when Howlett and colleagues[3] identified and characterized the distinct cannabinoid receptor in rat brain. The antagonizing effect of cannabinoids in the male reproductive system and physiology can be dated to 1974 where experimental models in male rats showed depression of spermatogenesis[21] and decrease in circulating testosterone levels.[22] 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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570006: Prostate carcinoma is a major life-threatening disease in men and WHO predicts that deaths from this type of cancer will double over the next 30 years (Bahnson, 2007; Jemal et al., 2009). Hence, novel therapeutic approaches are urgently required. Endocannabinoids, through interaction with CB1 receptors and synthetic endocannabinoid-vanilloid hybrids via stimulation of TRPV1 channels have been shown to inhibit nerve growth factor (NGF)-induced proliferation of human prostate PC-3 cells (Melck et al., 2000). However, THC can induce apoptosis of these cells via a receptor-independent mechanism (Ruiz et al., 1999), but also increase the production of the pro-proliferative factor, NGF (Velasco et al., 2001). A role for CB2 receptors in the induction of prostate carcinoma cell (PCC) apoptosis has been described (Sarfaraz et al., 2005; Olea-Herrero et al., 2009). On the other hand, the prototype TRPV1 agonist, capsaicin, produces both pro-proliferative and pro-apoptotic effects on PCCs (Sanchez et al., 2005; 2006; Czifra et al., 2009; Ziglioli et al., 2009; Malagarie-Cazenave et al., 2009; 2011) and not necessarily via TRPV1 activation, but depending on the sensitivity of the cells to androgen. Moreover, it has been suggested that other TRP channels play a role in PCC survival. TRP channels of melastatin-type 8 (TRPM8) are over-expressed in androgen-dependent PCC lines in a manner dependent on androgen receptor (AR) activation (Horoszewicz et al., 1983; Tsavaler et al., 2001; Henshall et al., 2003; Zhang and Barritt, 2004; Bidaux et al., 2005; 2007). In contrast, TRP channel of vanilloid type-2 (TRPV2) are down-regulated by AR, and their activation stimulates PCC migration (Monet et al., 2010). These findings are relevant to current investigations of the anti-tumour activity of non-THC cannabinoids, as many such compounds and the corresponding BDS antagonize TRPM8 channels and activate and subsequently desensitize TRPV2 and TRPV1 channels (Qin et al., 2008; De Petrocellis et al., 2008; 2011). Furthermore, most of these compounds are also able to inhibit endocannabinoid inactivation (De Petrocellis et al., 2011). Therefore, they might act as ‘indirect’ cannabinoid receptor agonists, similar to synthetic compounds previously found to inhibit PCC growth (Nomura et al., 2011).
https://www.ncbi.nlm.nih.gov/pubmed/12746841: ANA induced a decrease of EGFR levels on LNCaP, DU145, and PC3 prostatic cancer cells by acting through cannabinoid CB(1) receptor subtype and this leaded to an inhibition of the EGF-stimulated growth of these cells. Moreover, the G(1) arrest of metastatic DU145 and PC3 growth was accompanied by a massive cell death by apoptosis and/or necrosis while LNCaP cells were less sensitive to cytotoxic effects of ANA. The apoptotic/necrotic responses induced by ANA on these prostatic cancer cells were also potentiated by the acidic ceramidase inhibitor, N-oleoylethanolamine and partially inhibited by the specific ceramide synthetase inhibitor, fumonisin B1 indicating that these cytotoxic actions of ANA might be induced via the cellular ceramide production. The potent anti-proliferative and cytotoxic effects of ANA on metastatic prostatic cancer cells might provide basis for the design of new therapeutic agents for effective treatment of recurrent and invasive prostatic cancers.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339795: Cannabis sativa and its main active component delta-9-THC have long been used for numerous purposes throughout history including medicinal, textile, and recreational. Since its legal banning in the United States in 1937, it has become an issue of taboo and controversy, frowned upon for its recreational uses and psychotropic effects. Nonetheless, the endocannabinoid signaling system has recently been the focus of medical research and considered a potential therapeutic target[15–17] since the late 1980s when Howlett and colleagues[3] identified and characterized the distinct cannabinoid receptor in rat brain. The antagonizing effect of cannabinoids in the male reproductive system and physiology can be dated to 1974 where experimental models in male rats showed depression of spermatogenesis[21] and decrease in circulating testosterone levels.[22] 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.
https://www.ncbi.nlm.nih.gov/pubmed/22594963: Cannabidiol (CBD) significantly inhibited cell viability. Other compounds became effective in cells deprived of serum for 24 h. Several BDS were more potent than the pure compounds in the presence of serum. CBD-BDS (i.p.) potentiated the effects of bicalutamide and docetaxel against LNCaP and DU-145 xenograft tumours and, given alone, reduced LNCaP xenograft size. CBD (1-10 µM) induced apoptosis and induced markers of intrinsic apoptotic pathways (PUMA and CHOP expression and intracellular Ca(2+)). In LNCaP cells, the pro-apoptotic effect of CBD was only partly due to TRPM8 antagonism and was accompanied by down-regulation of AR, p53 activation and elevation of reactive oxygen species. LNCaP cells differentiated to androgen-insensitive neuroendocrine-like cells were more sensitive to CBD-induced apoptosis. These data support the clinical testing of CBD against prostate carcinoma.
https://www.ncbi.nlm.nih.gov/pubmed/23755281: 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.
Phosphorylated Akt immunoreactivity (pAkt-IR) scores were available in the database. CB₁ receptor immunoreactivity (CB₁IR) was rescored from previously published data using the same scale as pAkt-IR. There was a highly significant correlation between CB₁IR and pAkt-IR. Further, cases with high expression levels of both biomarkers were much more likely to have a more severe form of the disease at diagnosis than those with low expression levels. The two biomarkers had additive effects, rather than an interaction, upon disease-specific survival.
The present study provides data that is consistent with the hypothesis that at a high CB₁ receptor expression, the Akt signalling pathway becomes operative.
Cannabis -vs- Prostate Cancer