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Cannabinoid Receptor as a Novel Target for the Treatment of Prostate Cancer

Department of Dermatology, University of Wisconsin, Madison, Wisconsin

Requests for reprints: Hasan Mukhtar, Department of Dermatology, University of Wisconsin, Medical Sciences Center, Room B-25, 1300 University Avenue, Madison, WI 53706. Phone: 608-263-3927; Fax: 608-263-5223; E-mail: hmukhtar{at}wisc.edu.

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 CWR22R1 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 µmol/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 µmol/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.

Key Words: Cannabinoid • WIN-55,212-2 • PSA • AR

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