Abstract
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.
Keywords: Prostate cancer, castrate-resistant disease, chemotherapeutic agent, proteolytic activity, microtubule assembly, Bcl-2 family, tumor progression, cyclopentadienyl (Cp) ligands, anti-tumor metallocenes, Titanocene Derivatives, Docetaxel, IAPs, Bcl-2, Id-1, Apoptosis
Letters in Drug Design & Discovery
Title: Manipulating the Ability of Substituted Titanocene Derivatives to Induce Apoptosis in Castrate-Resistant Prostate Cancer Cells
Volume: 9 Issue: 3
Author(s): Catherine M. Dowling, Sandra Cuffe, Matthias Tacke, Anthony Deally, Megan Hogan, John M. Fitzpatrick and R. William G. Watson
Affiliation:
Keywords: Prostate cancer, castrate-resistant disease, chemotherapeutic agent, proteolytic activity, microtubule assembly, Bcl-2 family, tumor progression, cyclopentadienyl (Cp) ligands, anti-tumor metallocenes, Titanocene Derivatives, Docetaxel, IAPs, Bcl-2, Id-1, Apoptosis
Abstract: 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.
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M. Dowling Catherine, Cuffe Sandra, Tacke Matthias, Deally Anthony, Hogan Megan, M. Fitzpatrick John and William G. Watson R., Manipulating the Ability of Substituted Titanocene Derivatives to Induce Apoptosis in Castrate-Resistant Prostate Cancer Cells, Letters in Drug Design & Discovery 2012; 9 (3) . https://dx.doi.org/10.2174/157018012799129891
DOI https://dx.doi.org/10.2174/157018012799129891 |
Print ISSN 1570-1808 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-628X |
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