In vivo evaluation of AT-101 (R-(-)-gossypol acetic acid) in androgen independent growth of VCaP prostate cancer cells in combination with surgical castration

Robert D Loberg, Natalie McGregor, Chi Ying, Erin Sargent and Kenneth J Pienta

Year 2007, Volume 9, Issue 12

Abstract

Up-regulation of Bcl-2 family members is a well established mechanism in the development of androgen independent prostate cancer. We have established a prostate cancer model with VCaP prostate cancer cells in vivo to study the transition to androgen independence. Here we investigated the efficacy of AT-101 (a pan small molecule inhibitor of Bcl-2, Bcl-xL, and Mcl-1) in combination with surgical castration to delay the onset of androgen independent growth in vivo. AT-101 (15 mg/Kg, p.o. 5 days/week) in combination with surgical castration delayed the onset of androgen independent prostate cancer growth in vivo. In addition, we demonstrate the induction of Caspase-9 and Caspase-3 dependent induction of apoptosis following AT-101 treatment in vitro which was accompanied by an AT-101 induced down-regulation of Bcl-2 and Mcl-1 mRNA and protein expression. The presence of dihydrotestosterone (DHT) rescued the AT-101 induced apoptosis in vitro in VCaP cells placed in androgen depleted media but had no effect on AT-101 induced down-regulation of Bcl-2 and Mcl-1. We conclude that AT-101 in combination with surgical castration delays the onset of androgen independent prostate cancer in vivo by disrupting the anti-apoptotic activity of Bcl-2 up-regulation during the transition to androgen independence.

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