Type

Journal Article

Authors

Martin Clynes
Michael Gottesman
John J O'Leary
Jean-Pierre Gillet
Sandra Roche
Victoria McEneaney
Britta Kristina Stordal
Marion Hamon

Subjects

Medicine & Nursing

Topics
low density paclitaxel cisplatin cell lines genes brca1 cell line ovarian neoplasms drug effects biomarkers biological markers stress response cation transport proteins cancer patients humans glutathione cancer cell antineoplastic agents female genetics p gp metabolic networks and pathways metabolism gene expression regulation neoplastic drug resistance neoplasm cell line tumor p glycoproteins pharmacology ovarian cancer copper transporter 1

Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein (2012)

Abstract The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of Pglycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be upregulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.
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Full list of authors on original publication

Martin Clynes, Michael Gottesman, John J O'Leary, Jean-Pierre Gillet, Sandra Roche, Victoria McEneaney, Britta Kristina Stordal, Marion Hamon

Experts in our system

1
Martin Clynes
Dublin City University
Total Publications: 209
 
2
John O'Leary
Trinity College Dublin
Total Publications: 82
 
3
Victoria McEneaney
Maynooth University
Total Publications: 5
 
4
Britta Kristina Stordal
Trinity College Dublin
Total Publications: 28