Abstract A226: Mechanism of action of iniparib: Stimulation of reactive oxygen species (ROS) production in an iniparib-sensitive breast cancer cell line.

Abstract

Abstract Iniparib (BSI-201) holds substantial promise as an anti-cancer agent, and knowledge about its mechanism of bioactivity is evolving. While PARP inhibition has been proposed as iniparib's primary mechanism of action, the low potency of iniparib against PARP observed in a number of assays and models suggests that other mechanisms account for its bioactivity. These mechanisms are likely to include metabolic conversion of iniparib to a bioactive species. Here, we present an integrated analysis of profiling experiments (transcriptional and proteomic) and synergy screens (bioactive compound and shRNA) designed to identify the pathways associated with iniparib bioactivity. Proteomic and transcriptional profiling in MDA-MB-453 cells indicate that, at concentrations close to its in vitro potency as a cytotoxic agent, iniparib induces activation of the Nrf2 transcription factor, a known mediator of cellular anti-oxidant/anti-xenobiotic defense. Furthermore, Gene Set Enrichment Analysis (GSEA) comparing iniparib's transcriptional profile to drugs with known mechanism of action reveals similarity between iniparib and inhibitors of the mitochondrial electron transport chain. Bioactive compound and shRNA synergy screens also identify both Nrf2 and the components of the mitochondrial electron transport chain as genes required for maximum iniparib bioactivity. Cell-based imaging studies indicate that iniparib stimulates the production of reactive oxygen species (ROS). Taken together, these results are consistent with a mechanism in which a component of the Nrf2-mediated antioxidant response and/or the mitochondrial electron transport chain converts iniparib to its putative active metabolite, and this metabolite uncouples electron transport from oxidative phosphorylation, leading to the production of ROS at cytotoxic levels. The results of the integrated analysis may assist in the discovery of biomarkers for iniparib sensitivity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A226.