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J Pharm Sci. 2014 Jun;103(6):1913-20. doi: 10.1002/jps.23952. Epub 2014 Apr 3.

PARP Inhibitors as P-glyoprotein Substrates.

Author information

1
Department of Histopathology, St James' Hospital and Trinity College, Dublin, Dublin 8, Ireland.

Abstract

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.

KEYWORDS:

CEP-8983; P-glycoprotein; PARP inhibitor; cancer chemotherapy; cell lines; drug Resistance; olaparib; toxicity; veliparib

PMID:
24700236
DOI:
10.1002/jps.23952
[Indexed for MEDLINE]

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