Cannabinoid Receptors: A Novel Target for Therapy of Prostate Cancer
Annual rept., 19 Jan 2006-18 Jan 2007
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In recent years, cannabinoids, the active components of Cannabis sativa linnaeus marijuana and their derivatives are drawing renewed attention because of their diverse pharmacological activities such as cell growth inhibition and tumor regression. We have shown that the expression levels of both cannabinoid receptors CB1 and CB2 are higher in human prostate cancer cells than in normal prostate epithelial cells and treatment of LNCaP cells with WIN-55,212-2 WIN resulted in inhibition of cell growth and induction of apoptosis. Next study was conducted to understand the mechanistic basis of these effects. Treatment of LNCaP cells with WIN resulted in 1 an arrest of the cells in the G0G1 phase of the cell cycle 2 an induction of p53 p27KIP1 3 down-regulation of cyclins D1, D2, E, decrease in the expression of cdk -2, -4, and -6 4 decrease in protein expression of pRb 5 down-regulation of E2F 1-4 and 6 decrease in the protein expression of DP1 and DP2. Similar effects were also observed when androgen-independent PC3 cells were treated with WIN5-30 micrometers. We further observed sustained up regulation of ERK12, and inhibition of PI3kAkt pathways in WIN-55,212-2 treated cells. Inhibition of ERK12 abrogated WIN induced cell death suggesting that sustained activation of ERK12 leads to cell-cycle dysregulation and arrest of cells in G0G1 phase subsequently leading to an induction of apoptosis. Further, WIN treatment of cells resulted in a dose-dependent increase in BaxBcl-2 ratio in such a way that favors apoptosis. The induction of apoptosis proceeded through down regulation of caspases 3, 6, 7, and 9 and cleavage of PARP. Based on these data we suggest that cannabinoid receptor agonists should be considered as novel agents for the management of prostate cancer.
- Medicine and Medical Research