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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Paclitaxel
Ovarian Neoplasms
Pharmaceutical Preparations
Doxorubicin
Verapamil
Drug Therapy
Prescriptions
Carboplatin
P-Glycoprotein
olaparib
Cisplatin
Western Blotting
Cell Line
Polymerase Chain Reaction
Membranes
rucaparib

Keywords

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

Cite this

Vaidyanathan, Aparajitha ; Sawers, Lynne ; Gannon, Anne-Louise ; Chakravarty, Probir ; Scott, Alison L. ; Bray, Susan E. ; Ferguson, Michelle J. ; Smith, Gillian. / ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells. In: British Journal of Cancer. 2016 ; Vol. 115. pp. 431-441.
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ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells. / Vaidyanathan, Aparajitha; Sawers, Lynne; Gannon, Anne-Louise; Chakravarty, Probir; Scott, Alison L.; Bray, Susan E.; Ferguson, Michelle J.; Smith, Gillian (Lead / Corresponding author).

In: British Journal of Cancer, Vol. 115, 09.08.2016, p. 431-441.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells

AU - Vaidyanathan, Aparajitha

AU - Sawers, Lynne

AU - Gannon, Anne-Louise

AU - Chakravarty, Probir

AU - Scott, Alison L.

AU - Bray, Susan E.

AU - Ferguson, Michelle J.

AU - Smith, Gillian

PY - 2016/8/9

Y1 - 2016/8/9

N2 - 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.

AB - 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.

KW - ovarian cancer

KW - drug resistance

KW - chemotherapy

KW - paclitaxel

KW - olaparib

KW - PARP inhibitor

KW - ABCB1

KW - MDR1

KW - P-glycoprotein

U2 - 10.1038/bjc.2016.203

DO - 10.1038/bjc.2016.203

M3 - Article

VL - 115

SP - 431

EP - 441

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

ER -