Failure of Iniparib to Inhibit Poly(ADP-ribose) Polymerase in Vitro
Menée in vitro, cette étude montre que, à la différence de l'olaparib et du veliparib, l'activité de l'iniparib ne s'explique pas par un mécanisme inhibiteur de PARP
Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination- (HR-) deficient tumors and ability to enhance the action of certain DNA damaging agents. Compared to other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were performed to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib. Experimental Design: The abilities of iniparib, olaparib and veliparib to i) selectively induce apoptosis or inhibit colony formation in HR-deficient cell lines, ii) selectively sensitize HR-proficient cells to topoisomerase I poisons and iii) inhibit formation of poly(ADP-ribose) polymer in intact cells were compared. Results: Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier-generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons campto-thecin and topotecan. Finally, olaparib and veliparib inhibited formation of poly(ADP-ribose) polymer in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit poly(ADP-ribose) polymer formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine or paclitaxel. Conclusions: While iniparib kills normal and neoplastic cells at high (>40 uM) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.