Targeting bcl-2 gene to delay androgen-independent progression and enhancechemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides

Bcl-2 expression is upregulated in prostate cancer cells after androgen wit hdrawal and is associated with the development of androgen independence and chemoresistance. Induction of apoptotic cell death after androgen ablation , or chemotherapy, may be enhanced through functional inhibition of bcl-2. In this report, we tested the effects of antisense bcl-2 oligodeoxynucleoti des (ODN) with androgen ablation and taxane therapy on time to androgen-ind ependent (Al) progression in the androgen-dependent Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with 500 nmol/L antisense bcl-2 ODN decreased bcl-2 mRNA by 85%, compared with treatment with 500 nmol/L mi smatch control ODN. Although bcl-2 expression levels in Shionogi cells were not changed by docetaxel treatment, docetaxel treatment induced bcl-2 phos phorylation. Consequently, the formation of bcl-2/Bax heterodimer formation was inhibited in a dose-dependent manner. Treatment of Shionogi tumors in vitro with either 500 nmol/L antisense bcl-2 ODN or 10 nmol/L docetaxel alo ne did not induce apoptosis or reduce growth rates. However, combined treat ment reduced the concentration that reduces cell viability by 50% (IC50) of docetaxel from 100 nmol/L to 10 nmol/L and induced characteristic apoptoti c DNA laddering and cleavage of the poly(ADP-ribose)polymerase (PARP) prote in. Adjuvant in vivo administration of antisense bcl-2 ODN and polymeric mi cellar paclitaxel after castration resulted in a significant delay in time to Al recurrence when compared with administration of either agent alone. F urthermore, combined treatment of mice bearing Al recurrent Shionogi tumors with antisense bcl-2 ODN and micellar paclitaxel synergistically induced t umor regression and growth inhibition when compared with treatment with eit her agent alone. These findings suggest that down-regulation of bcl-2 by an tisense ODN chemosensitizes Al Shionogi tumors to taxanes, over and above t he effects of taxane-induced phosphorylation of bcl-2. Antisense bcl-2 ODN combined with taxanes may be a novel approach to the treatment of both esta blished and emerging Al disease. 1999. (C) 1999, Elsevier Science Inc.