AT-101 (R-(-)-Gossypol Acetic Acid) Enhances the Effectiveness of Androgen Deprivation Therapy in the VCaP Prostate Cancer Model

Prostate cancer remains a leading cause of cancer death in American men Androgen deprivation therapy (ADT) is the most common treatment for advanced prostate cancer patients: however. ADT fails in nearly all cases resulting in castration resistant or androgen-insensitive (AI) disease. In many cases, this progression results from dysregulation of the pro-survival Bcl-2 family proteins Inhibition or pro-survival Bcl-2 family proteins, therefore, may be an effective strategy to delay the onset of AI disease. Gossypol, a small molecule inhibitor of pro-survival Bcl-2 family proteins, has been demonstrated to inhibit AI prostate cancer growth. The apoptotic effect or gossypol, however, has been demonstrated to be attenuated by the presence or androgen in a prostate cancer xenograft mouse model (Vertebral Cancer of Prostate [VCaP]) treated with AT-101 (R-(-)-gossypol acetic acid) This study was undertaken to better understand the in vitro effects of androgen receptor (AR) on AT-101-induced apoptosis VCaP cells treated with AT-101 demonstrated an increase in apoptosis and downregulation of Bcl-2 pro-survival proteins. Upon AR activation in combination with AT-101 treatment, apoptosis is reduced, cell survival increases, and caspase activation is attenuated Akt and X inhibitor of apoptosis (XIAP) are downregulated in the presence of AT-101, and AR stimulation rescues protein expression Combination treatment of bicalutamide and AT-101 increases apoptosis by reducing the expression of these pro-survival proteins. These data suggest that combination therapy or AT-101 and ADT may further delay the onset of AI disease, resulting in prolonged progression-free survival of prostate cancer patients. J. Cell Biochem 110 1187-1194, 2010. 2010 Wiley-lass. Inc