Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10162505 | Journal of Pharmaceutical Sciences | 2014 | 8 Pages |
Abstract
The cytotoxicity of PARP inhibitors olaparib, veliparib, and CEP-8983 were investigated in two P-glycoprotein (P-gp) over-expressing 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 103:1913-1920, 2014
Keywords
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Authors
Denise Lawlor, Patricia Martin, Steven Busschots, Julien Thery, John J. O'leary, Bryan T. Hennessy, Britta Stordal,