Cannabinoid Receptors: A Novel Target for Therapy for Prostate Cancer; Final rept. 19 Jan 2004-18 Jan 2008

摘要

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 i) an arrest of the cells in the G0/G1 phase of the cell cycle; ii) an induction of p53 & p27/KIP1; iii) down- regulation of cyclins decrease in the expression of cdks; iv) decrease in protein expression of pRb; v) down-regulation of E2F (1-4); and vi) decrease in the protein expression of DP1 and DP2. Similar effects were also observed when androgen-independent PC3 cells were treated with WIN(5-30 microM). We further observed sustained up regulation of ERK1/2, and inhibition of PI3k/Akt pathways in WIN-55,212-2 treated cells. Inhibition of ERK1/2 abrogated WIN indued cell death suggesting that sustained activation of ERK1/2 leads to cell-cycle dysregulation and arrest of cells in G0/G1 phase subsequently leading to an induction of apoptosis. Further, WIN treatment of cells resulted in a dose- dependent increase in Bax/Bcl-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. To establish in vivo relevance of these in vitro findings, we implanted athymic nude mice with androgen-responsive CWR22R 1 cells which form rapid tumors and secrete PSA in the blood stream of the host. As compared to untreated animals, WIN treated mice (0.5 mg/kg b.wt, i.p, alternate day) exhibited significant inhibition in the tumor growth with significant reduction in PSA secretion in the serum. In animals without WIN treatment, targeted tumor volume of 1200 mm3 was reached at 35 days post-tumor inoculation; whereas this tumor volume was attained in 51 days in WIN treated.