Characterisation and Manipulation of Docetaxel Resistant Prostate Cancer Cell Lines

Hdl Handle:
http://hdl.handle.net/10147/181993
Title:
Characterisation and Manipulation of Docetaxel Resistant Prostate Cancer Cell Lines
Authors:
O'Neill, Amanda J; Prencipe, Maria; Dowling, Catherine; Fan, Yue; Mulrane, Laoighse; Gallagher, William M; O'Connor, Darran; O'Connor, Robert; Devery, Aoife; Corcoran, Claire; Rani, Sweta; O'Driscoll, Lorraine; Fitzpatrick, John M; Watson, R. William G
Citation:
Molecular Cancer. 2011 Oct 07;10(1):126
Issue Date:
7-Oct-2011
URI:
http://hdl.handle.net/10147/181993
Abstract:
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-κB activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF-κB activity and IκB phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF-κB 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-κB plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target.
Item Type:
Journal Article

Full metadata record

DC FieldValue Language
dc.contributor.authorO'Neill, Amanda J-
dc.contributor.authorPrencipe, Maria-
dc.contributor.authorDowling, Catherine-
dc.contributor.authorFan, Yue-
dc.contributor.authorMulrane, Laoighse-
dc.contributor.authorGallagher, William M-
dc.contributor.authorO'Connor, Darran-
dc.contributor.authorO'Connor, Robert-
dc.contributor.authorDevery, Aoife-
dc.contributor.authorCorcoran, Claire-
dc.contributor.authorRani, Sweta-
dc.contributor.authorO'Driscoll, Lorraine-
dc.contributor.authorFitzpatrick, John M-
dc.contributor.authorWatson, R. William G-
dc.date.accessioned2011-10-28T11:11:12Z-
dc.date.available2011-10-28T11:11:12Z-
dc.date.issued2011-10-07-
dc.identifierhttp://dx.doi.org/10.1186/1476-4598-10-126-
dc.identifier.citationMolecular Cancer. 2011 Oct 07;10(1):126-
dc.identifier.urihttp://hdl.handle.net/10147/181993-
dc.description.abstractAbstract 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-κB activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF-κB activity and IκB phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF-κB 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-κB plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target.-
dc.titleCharacterisation and Manipulation of Docetaxel Resistant Prostate Cancer Cell Lines-
dc.typeJournal Article-
dc.language.rfc3066en-
dc.rights.holderO'Neill et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2011-10-27T19:10:17Z-
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