Document Detail


Effects of titanocene dichloride derivatives on prostate cancer cells, specifically DNA damage-induced apoptosis.
MedLine Citation:
PMID:  20665530     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Sandra Cuffe; Catherine M Dowling; James Claffey; Clara Pampillón; Megan Hogan; John M Fitzpatrick; Michael P Carty; Matthias Tacke; R William G Watson
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Prostate     Volume:  71     ISSN:  1097-0045     ISO Abbreviation:  Prostate     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2010-12-24     Completed Date:  2011-01-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8101368     Medline TA:  Prostate     Country:  United States    
Other Details:
Languages:  eng     Pagination:  111-24     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Wiley-Liss, Inc.
Affiliation:
UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland. sandra.cuffe@ucd.ie
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*,  genetics
Blotting, Western
Cell Line, Tumor
Cell Survival / drug effects
Comet Assay
DNA Damage*
Gentian Violet / chemistry
Humans
Male
Neoplasms, Hormone-Dependent / drug therapy,  genetics,  pathology
Organometallic Compounds / pharmacology*
Prostatic Neoplasms / drug therapy*,  genetics,  pathology
Titanium / chemistry
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Organometallic Compounds; 0/Titanocene Y; 0/bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV); 1271-19-8/titanocene dichloride; 548-62-9/Gentian Violet; 7440-32-6/Titanium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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