PARP Inhibitors as P-glyoprotein Substrates
2014; Elsevier BV; Volume: 103; Issue: 6 Linguagem: Inglês
10.1002/jps.23952
ISSN1520-6017
AutoresDenise Lawlor, P.J. Martin, Steven Busschots, Julien Thery, John O’Leary, Bryan T. Hennessy, Britta Stordal,
Tópico(s)Integrated Circuits and Semiconductor Failure Analysis
ResumoThe 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
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