ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells

Aparajitha Vaidyanathan, Lynne Sawers, Anne-Louise Gannon, Probir Chakravarty, Alison L. Scott, Susan E. Bray, Michelle J. Ferguson, Gillian Smith (Lead / Corresponding author)

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Abstract

Background: Clinical response to chemotherapy for ovarian cancer is frequently compromised by the development of drug-resistant disease. The underlying molecular mechanisms and implications for prescription of routinely prescribed chemotherapy drugs are poorly understood.

Methods: We created novel A2780-derived ovarian cancer cell lines resistant to paclitaxel and olaparib, following continuous incremental drug selection. MTT assays were used to assess chemosensitivity to paclitaxel and olaparib in drug-sensitive and drug-resistant cells ± the ABCB1 inhibitors verapamil and elacridar, and cross-resistance to cisplatin, carboplatin, doxorubicin, rucaparib, veliparib and AZD2461. ABCB1 expression was assessed by qRT-PCR, copy number, Western blot and immunohistochemical analysis and ABCB1 activity assessed by Vybrant™ and P-glycoprotein-Glo™ assays.

Results: Paclitaxel-resistant cells were cross-resistant to olaparib, doxorubicin and rucaparib, but not veliparib or AZD2461. Resistance correlated with increased ABCB1 expression, and was reversible following treatment with the ABCB1 inhibitors verapamil and elacridar. Active efflux of paclitaxel, olaparib, doxorubicin and rucaparib was confirmed in drug-resistant cells and in ABCB1-expressing bacterial membranes.

Conclusion: We describe a common ABCB1-mediated mechanism of paclitaxel and olaparib resistance in ovarian cancer cells. Optimal choice of PARP inhibitor may therefore limit the progression of drug resistant disease, while routine prescription of first-line paclitaxel may significantly limit subsequent chemotherapy options in ovarian cancer patients.
Original languageEnglish
Pages (from-to)431-441
Number of pages11
JournalBritish Journal of Cancer
Volume115
Early online date14 Jul 2016
DOIs
Publication statusPublished - 9 Aug 2016

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Keywords

  • ovarian cancer
  • drug resistance
  • chemotherapy
  • paclitaxel
  • olaparib
  • PARP inhibitor
  • ABCB1
  • MDR1
  • P-glycoprotein

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