2K-CAP (a novel bis-benzylisoquinoline alkaloid) decreases prostate-specific antigen and induces Go/G1 cell cycle growth arrest of prostate carcinoma cells: implications for prostate cancer intervention

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Prostate cancer is the second leading cause of cancer deaths in men. Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for human prostate cancer intervention. We investigated the effects of 2K-CAP, a novel derivative of tetrandrine (an active constituent of Chinese herb S. tetrandra) on PSA secretion and cell growth and proliferation in LNCaP cells, a line of hormone sensitive prostate cancer cells. Treatment of LNCaP cells with 2K-CAP resulted in significant decrease in PSA synthesis and secretion. Treatment of cells with charcoal stripped serum and 5α-dihyroxy testosterone showed that 2K-CAP treatment inhibited androgen stimulated PSA secretion and down regulation of androgen receptor levels. 2K-CAP also suppressed the growth and proliferation of LNCaP cells. These effects of 2K-CAP on inhibition of growth and proliferation were time ( 24-96h) and concentration (5-20 μM) dependent. We also show that 2K-CAP treatment inhibited growth and proliferation of LNCaP cells stimulated by androgens as well as complete Fetal Calf Serum. These results demonstrate that 2K-CAP treatment had profound effect on androgen dependent as well as growth factor stimulated growth and proliferation of prostate cancer cells. 2K-CAP treatment resulted in increase in Rip/p21 levels with no effect on p27/Kip. Cell Cycle analysis revealed that 2 K-CAP treatments increased the number of cells in Go/G1-phase of the cell cycle, consistent with G1/Go arrest. Taken together these studies demonstrate that 2K-CAP causes growth arrest of LNCaP cells by inhibiting cell cycle in Go/G1 phase, and inhibiting PSA synthesis and secretion. These results demonstrate that 2K-CAP as a potential agent for intervention of prostate cancer.