Cannabinoid Receptors: A Novel Target for Therapy of Prostate Cancer

Cannabinoids, the active components of Cannabis sativaLinnaeus (marijuana) and their derivatives have receivedrenewed interest in recent years due to their diversepharmacologic activities such as cell growth inhibition,anti-inflammatory effects and tumor regression. Here weshow that expression levels of both cannabinoid receptors,CB1 and CB2, are significantly higher in CA-human papillo-mavirus-10 (virally transformed cells derived from adeno-carcinoma of human prostate tissue), and other humanprostate cells LNCaP, DUI45, PC3, and CWR22RN1 than inhuman prostate epithelial and PZ-HPV-7 (virally transformedcells 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 Mmol/L) andtime-dependent (24-48 hours) inhibition of cell growth,blocking of CB1 and CB2 receptors by their antagonistsSR141716 (CB1) and SR144528 (CB2) significantly preventedthis effect. Extending this observation, we found that WIN-55,212-2 treatment with LNCaP resulted in a dose(1-10Mmol/L) and time-dependent (24-72 hours) induction ofapoptosis (a), decrease in protein and mRNA expression ofandrogen receptor (b), decrease in intracellular protein andmRNA expression of prostate-specific antigen (c), decrease insecreted prostate-specific antigen levels (d), and decrease inprotein expression of proliferation cell nuclear antigen andvascular endothelial growth factor (e). Our results suggestthat WIN-55,212-2 or other non–habit-forming cannabinoidreceptor agonists could be developed as novel therapeuticagents for the treatment of prostate cancer. (Cancer Res 2005;65(5): 1635-41)