PARP Inhibitors as P-glyoprotein Substrates.

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.

• Authors: Denise Lawlor, Patricia Martin, Steven Busschots, Julien Thery, John J O'Leary, Bryan T Hennessy, Britta Stordal
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 103 Issue 6 Pg. 1913-20 (Jun 2014) ISSN: 1520-6017 [Electronic] United States
• PMID: 24700236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Enzyme Inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Cell Line, Tumor
• Enzyme Inhibitors (metabolism, pharmacology)
• Humans
• Poly(ADP-ribose) Polymerase Inhibitors