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Title: Stilbenes inhibit androgen receptor expression in 22Rv1 castrate-resistant prostate cancer cells

Author
item KUMAR, AVINASH - University Of Mississippi Medical Center
item LIN, SHIH-YUN - University Of Mississippi Medical Center
item DHAR, SWATI - University Of Mississippi Medical Center
item Rimando, Agnes
item LEVENSON, ANAIT - University Of Mississippi Medical Center

Submitted to: Journal of Medicinally Active Plants
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/23/2014
Publication Date: 12/29/2014
Publication URL: http://handle.nal.usda.gov/10113/62341
Citation: Kumar, A., Lin, S., Dhar, S., Rimando, A.M., Levenson, A.S. 2014. Stilbenes inhibit androgen receptor expression in 22Rv1 castrate-resistant prostate cancer cells. Journal of Medicinally Active Plants. 3(1-4):1-8.

Interpretive Summary: The positive correlation between levels of male hormone and prostate tumor growth is known, and male hormone deprivation (chemical castration) has become a main treatment option in advanced stage and recurring prostate cancer. Some patients demonstrate castrate resistance, defined as cancer progression despite serum testosterone levels less than 20 ng/dl, with male hormone deprivation therapy. Inhibition of the male hormone receptor plays an important role in preventing prostate cancer development and progression. We have previously shown that resveratrol (Res) inhibits male hormone-promoted growth, receptor expression and activation in hormone-responsive prostate cancer cells. In the current study, we investigated the effects of Res and three natural analogs: trimethoxy-resveratrol (3M-Res), pterostilbene (Pter) and piceatannol (Pic), on growth of castrate-resistant cells. These cells have both the full version of the receptor and the truncated form, which lacks the hormone binding site. Our results showed that 3M-Res was the most effective in inhibiting the growth of the cancer cells; however, it had no effect on the hormone receptor. On the other hand, Res, Pter and Pic inhibited both the full version and truncated form of the receptor, with effect on the truncated form being more prominent. Our results indicate both hormone receptor-independent (with 3M-Res) and possible hormone receptor-dependent (with Res, Pter, Pic) mechanisms of cell growth inhibition by these stilbenes. These findings provide evidence for the potential use of these stilbenes in arresting the progression of castrate-resistant prostate cancer.

Technical Abstract: Androgen receptor (AR) signaling plays an important role in the development and progression of prostate cancer (PCa). Importantly, AR continues to be expressed in advanced stages of castrate-resistant PCa (CRPC), where it can have ligand- independent activity. Identification of naturally occurring substances which can inhibit AR expression holds promise for PCa chemoprevention and therapy. We have previously shown that resveratrol (Res) inhibits androgen-promoted growth, AR expression and transactivation in androgen-responsive non-metastatic LNCaP PCa cells. In the current study, we investigated the effects of Res and its three natural analogs: trimethoxy-resveratrol (3M-Res), pterostilbene (Pter) and piceatannol (Pic) on growth of 22Rv1 castrate-resistant cells, which express wild type (AR114/110) and truncated form (AR80) of AR. We found that although all the stilbenes inhibited the proliferation of 22Rv1 cells in a dose-dependent manner, 3M-Res was the most potent inhibitor. We also found that while AR114/110 responded to the synthetic androgen agonist methyltrienolone (R1881) as well as to antiandrogen Flutamide AR80, which lacks ligand-binding domain, did not respond to R1881 but was inhibited by Flutamide. Interestingly, Res, Pter and Pic but not 3M-Res, like Flutamide, inhibited both AR114/110 and AR80, with the effect on AR80 being more prominent when high concentrations of the stilbenes were used. Taken together, these data indicate both AR-independent (3M-Res) and possible AR-dependent (Res, Pter, Pic) mechanisms of cell growth inhibition by these stilbenes. These findings provide evidence for the potential use of these stilbenes in arresting the progression of CRPC.