PARP inhibitors as P-glyoprotein substrates

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.

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