Effects of titanocene dichloride derivatives on prostate cancer cells, specifically DNA damage-induced apoptosis

• Published in: The Prostate 2011-02, Vol.71 (2), p.111-124
• Main Authors: Cuffe, Sandra, Dowling, Catherine M., Claffey, James, Pampillón, Clara, Hogan, Megan, Fitzpatrick, John M., Carty, Michael P., Tacke, Matthias, Watson, R. William G.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Cell Survival - drug effects; Comet Assay; DNA Damage; Gentian Violet - chemistry; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - genetics; Neoplasms, Hormone-Dependent - pathology; Nephrology. Urinary tract diseases; Organometallic Compounds - pharmacology; prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Titanium - chemistry; titanocene dichloride derivatives; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.21227

BACKGROUND While locally advanced prostate cancer is initially treatable with androgen ablation, eventually cells develop a castrate‐resistant phenotype. Currently, there are no effective treatments for this form of the disease with Docetaxel only providing a small survival advantage. In this study, the effects of novel derivatives of titanocene dichloride on prostate cancer cell lines has been investigated. METHODS Cellular effects were assessed using the crystal violet assay and the clonogenic survival assay. Cell cycle and apoptosis were assessed by propidium iodide staining. DNA damage was analyzed by comet assay and Western analysis. DNA damage response inhibition was achieved by pre‐incubation with an ATM/ATR inhibitor; CGK733 and DNA‐PK inhibitor; DMNB. RESULTS These analogs caused a reduction in cell number. In particular titanocene Y and C had significant effects in all cell lines. A reduction in clonogenic survival was found in response to titanocene Y in three cell lines while the PC‐3 cells exhibited increased resistance.Further analysis showed no effect on cell cycle however, the analogs were found to induce apoptosis in a dose‐dependent manner in all cell lines. These analogs associate with DNA, induce DNA damage and a differential damage response. Inhibition of key regulators of this DNA damage response sensitized the PC‐3 cell line to titanocene‐induced apoptosis and significantly reduced the clonogenic capacity of the cells. CONCLUSION These results demonstrate the mechanism of action of these novel titanocene dichloride analogs and their potential use in castrate‐independent advanced prostate cancer. Prostate 71: 111–124, 2011. © 2010 Wiley‐Liss, Inc.