PARP inhibitors as P-glyoprotein substrates

Lawlor, Denise, Martin, Patricia, Busschots, Steven, Thery, Julien, O'Leary, John J., Hennessy, Bryan T. and Stordal, Britta K. ORCID logoORCID: https://orcid.org/0000-0002-7892-951X (2014) PARP inhibitors as P-glyoprotein substrates. Journal of Pharmaceutical Sciences, 103 (6) . pp. 1913-1920. ISSN 0022-3549 [Article] (doi:10.1002/jps.23952)

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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.

Item Type: Article
Additional Information: Article first published online: 3 APR 2014
Keywords (uncontrolled): olaparib; veliparib; CEP-8983; PARP inhibitor; drug Resistance; cell lines; P-glycoprotein; cancer chemotherapy; toxicity
Research Areas: A. > School of Science and Technology > Natural Sciences > Biomarkers for Cancer group
Item ID: 14450
Notes on copyright: This is the pre-peer reviewed version of the following article: Lawlor, D., Martin, P., Busschots, S., Thery, J., O'Leary, J.J., Hennessy, B.T. and Stordal, B. (2014), PARP Inhibitors as P‐glyoprotein Substrates. J. Pharm. Sci., 103: 1913-1920, which has been published in final form at https://doi.org/10.1002/jps.23952. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
Useful Links:
Depositing User: Britta Stordal
Date Deposited: 13 Mar 2015 14:20
Last Modified: 08 Jun 2022 16:29
URI: https://eprints.mdx.ac.uk/id/eprint/14450

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