Manipulating the Ability of Substituted Titanocene Derivatives to Induce Apoptosis in Castrate-Resistant Prostate Cancer Cells

Castrate-resistant prostate cancer is associated with resistance to apoptotic-triggered cell death mediated by elevated expression of anti-apoptotic proteins. In the current study, the ability of three titanocene derivatives to induce apoptosis in PC-3 cells is investigated and compared to docetaxel as the standard therapy as a first step in the pre-clinical testing of these compounds against advanced prostate cancer. Apoptosis triggered by the titanocene derivatives and docetaxel was assessed using propidium iodide DNA staining by flow cytometry. Bcl-2, the IAPs and Id-1 were manipulated in PC-3 cells by siRNA strategies and their corresponding protein expression determined by western blotting. The ring-substituted titanocene derivatives induced apoptosis in a time and dose dependent manner in PC-3 cells similar to that seen with docetaxel. Triple IAP knockdown (cIAP-1, cIAP-2 and xIAP), Bcl-2 and Id-1 resulted in an increased sensitivity to apoptosis induced by the titanocene derivatives but no strategy sensitized to docetaxel-induced apoptosis. Down-regulation of Bcl-2, the IAPs and Id-1 may be potential target to increase sensitivity of castrate-resistant prostate cancer to the titanocene derivatives. It is vital not only to understand tumor biology, but also understand how individual drugs exert their effects. Combining this knowledge will ensure that we can effectively tailor therapeutic strategies for the treatment of androgen-independent prostate cancer.