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dc.contributor.authorO'TOOLE, SHARONen
dc.contributor.authorO'LEARY, JOHNen
dc.contributor.authorBUSSCHOTS, STEVENen
dc.date.accessioned2015-04-16T16:23:14Z
dc.date.available2015-04-16T16:23:14Z
dc.date.issued2014en
dc.date.submitted2014en
dc.identifier.citationBusschots S, O'Toole S, O'Leary JJ, Stordal B. , Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells, Experimental Cell Research, 2014, 1 - 14en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/73761
dc.descriptionPUBLISHEDen
dc.description.abstractA major risk factor for ovarian cancer is germline mutations of BRCA1/2. It has been found that (80%) of cellular models with acquired platinum or taxane resistance display an inverse resistance relationship, that is collateral sensitivity to the other agent. We used a clinically relevant comparative selection strategy to develop novel chemoresistant cell lines which aim to investigate the mechanisms of resistance that arise from different exposures of carboplatin and taxol on cells having BRCA1 function (UPN251) or dysfunction (OVCAR8). Resistance to carboplatin and taxol developed quicker and more stably in UPN251 (BRCA1-wildtype) compared to OVCAR8 (BRCA1-methylated). Alternating carboplatin and taxol treatment delayed but did not prevent resistance development when compared to single-agent administration. Interestingly, the sequence of drug exposure influenced the resistance mechanism produced. UPN251-6CALT (carboplatin first) and UPN251-6TALT (taxol first) have different profiles of cross resistance. UPN251-6CALT displays significant resistance to CuSO4 (2.3-fold, p=0.004) while UPN251-6TALT shows significant sensitivity to oxaliplatin (0.6-fold, p=0.01). P-glycoprotein is the main mechanism of taxol resistance found in the UPN251 taxane-resistant sublines. UPN251 cells increase cellular glutathione levels (3.0-fold, p=0.02) in response to carboplatin treatment. However, increased glutathione is not maintained in the carboplatin-resistant sublines. UPN251-7C and UPN251-6CALT are low-level resistant to CuSO4 suggesting alterations in copper metabolism. However, none of the UPN251 sublines have alterations in the protein expression of ATP7A or CTR1. The protein expression of BRCA1 and MRP2 is unchanged in the UPN251 sublines. The UPN251 sublines remain sensitive to parp inhibitors veliparib and CEP8983 suggesting that these agents are candidates for the treatment of platinum/taxane resistant ovarian cancer patienten
dc.description.sponsorshipThis study was funded by a PhD Scholarship from the Royal City of Dublin Hospital Trust (S.B.), the Emer Casey Foundation (S.B) as part of the DISCOVARY Consortium, an Irish Cancer Society Postdoctoral Fellowship (B.S.) and a Marie Curie Re-integration Grant from the European Union P7 programme (B.S.)en
dc.format.extent1en
dc.format.extent14en
dc.relation.ispartofseriesExperimental Cell Researchen
dc.rightsYen
dc.subjectResistance; Comparative; Selection strategy; Ovarian cancer; BRCA1; Carboplatin; Taxolen
dc.subject.lcshResistance; Comparative; Selection strategy; Ovarian cancer; BRCA1; Carboplatin; Taxolen
dc.titleCarboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cellsen
dc.typeJournal Articleen
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/busschosen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/olearyjjen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/shotooleen
dc.identifier.rssinternalid98537en
dc.identifier.doihttp://dx.doi.org/10.1016/j.yexcr.2014.12.001en
dc.rights.ecaccessrightsopenAccess


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