Targeting AR and Akt for the Treatment of Prostate Cancer

Radical prostectomy, radiation treatment, and/or hormone ablation therapy are the first line of treatment for prostate cancer (PCa). Despite initial sensitivity to these treatments, PCa eventually progresses to an androgen-independent PCa, which is both aggressive and refractory to current therapeutic options. Accordingly, there is a tremendous need for an agent, dosed alone or in combination with hormone ablation therapy, that can either retard or completely arrest the emergence of androgen independent PCa. Our preliminary studies demonstrate Withaferin-A (WA) , a natural compound that is orally bioavailable and non-toxic, targets AR-independent PCa cells (e.g., PC-3) by inhibiting phosphorylated Akt; this inhibitions leads to the activation of prostate apoptosis response-4 (Par-4)-dependent apoptosis in cell culture and in animal models. Similarly, inhibition of AR in AR-positive (AR+) PCa cells (e.g., LNCaP and 22Rv1) facilitates WA-induced Par-4 activation and apoptosis. Over-expression of either Akt or AR inhibits both WA-mediated Par-4 activation, as well as induction of apoptosis, in those cells. We have extended these results in vivo, showing WA, in combination with AR inhibitors, inhibits prostate tumor growth in xenografts and in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. These results suggest both AR and Akt signaling negatively regulate the pro-apoptotic functions of Par-4 in PCa cells, thereby undermining therapeutic approaches and promoting disease progression.