Type

Journal Article

Authors

R William G Watson
John M Fitzpatrick
Claire Corcoran
Aoife Devery
Robert O'Connor
Darran O'Connor
William M Gallagher
Laoighse Mulrane
Yue Fan
Catherine Dowling
and 4 others

Subjects

Medicine & Nursing

Topics
genes reporter genetics metabolism transcription factor nf b cell aging antineoplastic agents oncology drug therapy molecular targeted therapy cancer cell lines beta galactosidase cancer cell survival male biosynthesis sulfones prostate cancer pathology drug resistance neoplasm drug resistance pharmacology cell line tumor elacridar 3 4 methylphenylsulfonyl 2 propenenitrile apoptosis regulatory proteins nitriles nf kappa b cell lines apoptosis gene expression profiling anti apoptotic docetaxel taxoids drug effects humans p glycoprotein gene expression prostatic neoplasms antagonists inhibitors tetrahydroisoquinolines luciferases renilla acridines

Characterisation and manipulation of docetaxel resistant prostate cancer cell lines (2011)

Abstract Background: There is no effective treatment strategy for advanced castration-resistant prostate cancer. Although Docetaxel (Taxotere?) represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The aims of this study were to further investigate the mechanisms of resistance to Docetaxel. Three Docetaxel resistant sub-lines were generated and confirmed to be resistant to the apoptotic and anti-proliferative effects of increasing concentrations of Docetaxel. Results: The resistant DU-145 R and 22RV1 R had expression of P-glycoprotein and its inhibition with Elacridar partially and totally reversed the resistant phenotype in the two cell lines respectively, which was not seen in the PC-3 resistant sublines. Resistance was also not mediated in the PC-3 cells by cellular senescence or autophagy but multiple changes in pro- and anti-apoptotic genes and proteins were demonstrated. Even though there were lower basal levels of NF-?B activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF-?B activity and I?B phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF-?B with the BAY 11-7082 inhibitor reversed the resistance to Docetaxel. Conclusion: This study confirms that multiple mechanisms contribute to Docetaxel resistance and the central transcription factor NF-?B plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target.
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Full list of authors on original publication

R William G Watson, John M Fitzpatrick, Claire Corcoran, Aoife Devery, Robert O'Connor, Darran O'Connor, William M Gallagher, Laoighse Mulrane, Yue Fan, Catherine Dowling and 4 others

Experts in our system

1
R William G Watson
University College Dublin
Total Publications: 135
 
2
John M Fitzpatrick
University College Dublin
Total Publications: 129
 
3
Claire Corcoran
Trinity College Dublin
 
4
Robert O'Connor
Dublin City University
Total Publications: 74
 
5
Darran P O'Connor
Royal College of Surgeons in Ireland
Total Publications: 43
 
6
William M Gallagher
University College Dublin
Total Publications: 148
 
7
Laoighse Mulrane
University College Dublin
Total Publications: 10
 
8
Yue Fan
Royal College of Surgeons in Ireland
Total Publications: 14