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In Vivo Evaluation of AT-101 (R-(—)-Gossypol Acetic Acid) in Androgen-Independent Growth of VCaP Prostate Cancer Cells in Combination with Surgical Castration

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

Abstract

AbstractPURPOSE: Upregulation of Bcl-2 family members is a well-established mechanism in the development of androgen-independent prostate cancer. Inhibition of the antiapoptotic proteins Bcl-2 and Mcl-1 may delay the transition to androgen-independent growth. EXPERIMENTAL DESIGN: 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 (R-(—)-gossypol acetic acid; a pan small molecule inhibitor of Bcl-2, BCI-xL, Mcl-1) in combination with surgical castration to delay the onset of androgen-independent growth in vivo. RESULTS: AT-101 (15 mg/kg, per os (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 downregulation of Bcl-2 and Mcl-1 mRNA and protein expression. CONCLUSIONS: We conclude that AT-101 in combination with surgical castration delays the onset of androgen-independent prostate cancer in vivo by disrupting the antiapoptotic activity of BCl-2 upregulation during the transition to androgen independence. Further studies are needed to define the mechanism of action by which AT-101 attenuates the expression of Bcl-2 and Mcl-1 and to characterize the potential for AT-101 in combination with hormone therapy

Publisher: Neoplasia Press, Inc. Published by Elsevier Inc.
Year: 2007
DOI identifier: 10.1593/neo.07778
OAI identifier:

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