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 µM) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.

Liver transplantation from deceased or living human donors remains the only proven option for patients with end-stage liver disease. However, the shortage of donor organs is a significant clinical concern that has led to the pursuit of tissue-engineered liver grafts generated from decellularized liver extracellular matrix and functional cells. Investigative efforts on optimizing both liver decellularization and recellularization protocols have been made in recent decades. In the current review, we briefly summarize these advances, including the generation of high-quality liver extracellular matrix scaffolds, evaluation criteria for quality control, modification of matrix for enhanced properties, and reseeding strategies. These efforts to optimize the methods of decellularization and recellularization lay the groundwork towards generating a transplantable, human-sized liver graft for the treatment of patients with severe liver disease.