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.
Department of Histopathology, St James' Hospital and Trinity College, Dublin, Dublin 8, Ireland.
Denise
D
Lawlor
Patricia
P
Martin
Steven
S
Busschots
Julien
J
Thery
John J
JJ
O'Leary
Bryan T
BT
Hennessy
Britta
B
Stordal
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
CEP-8983; P-glycoprotein; PARP inhibitor; cancer chemotherapy; cell lines; drug Resistance; olaparib; toxicity; veliparib