Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 103, Issue 6, Pages 1913-1920Publisher
WILEY-BLACKWELL
DOI: 10.1002/jps.23952
Keywords
olaparib; veliparib; CEP-8983; PARP inhibitor; drug Resistance; cell lines; P-glycoprotein; cancer chemotherapy; toxicity
Funding
- Marie Curie Reintegration Grant from the European Union FP7 Programme
- Irish Cancer Society Postdoctoral Fellowship
- Translational Research Award from the Health Research Board
- Science Foundation Ireland
- Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology
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The cytotoxicity of PARP inhibitors olaparib, veliparib, and CEP-8983 were investigated in two P-glycoprotein (P-gp) overexpressing drug-resistant cell models (IGROVCDDP and KB-8-5-11). IGROVCDDP and KB-8-5-11 were both resistant to olaparib and resistance was reversible with the P-gp inhibitors elacridar, zosuquidar, and valspodar. In contrast, the P-gp overexpressing models were not resistant to veliparib or CEP-8983. Olaparib and veliparib did not induce protein expression of P-gp in IGROVCDDP or KB-8-5-11 at doses that successfully inhibit PARP. Olaparib therefore appears to be a P-gp substrate. Veliparib and CEP-8983 do not appear to be substrates. Veliparib and CEP-8983 may therefore be more useful in combined chemotherapy regimens with P-gp substrates and may be active in platinum and taxane-resistant ovarian cancer. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci
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