Abstract 1122: Lipoic acid analogs induce ROS, leading to potent mitochondrial enzyme inhibition, metabolic dysfunction and cell death in tumor cells

Abstract

Abstract The targeting of tumor cell metabolism has emerged as an attractive candidate for chemotherapeutics. In particular, tumor cell mitochondria are dramatically reprogrammed to generate large amounts of biosynthetic intermediates to fuel cell division. We previously described a novel class of non-redox active lipoic acid analogs (“thioctoids”) which effect dramatic inactivation of the mitochondrial enzyme complex pyruvate dehydrogenase (PDH) (PMID:21769686). We have recently completed a comprehensive metabolomic study indicating that thioctoids down-regulate multiple mitochondria-associated enzymes. Each of these target enzymes are key control points for entry of carbon into the TCA cycle, including the alpha-ketoglutarate dehydrogenase complex and the branch-chain dehydrogenase/amino trasferase complex. In addition we will present data that reactive oxygen species (ROS) play a direct regulatory role in these inactivations and are a major contributor to the resultant cell cycle arrest and multiple cell death pathways which follow. Taken together, our results indicate that thioctoids are potent inhibitors of tumor cell mitochondrial energy metabolism, owing, apparently, to the central regulatory role of lipoic acid in mitochondrial lipoamide dehydrogenase-containing enzyme complexes. We hypothesize that thioctoids are ‘misread’ by these complexes resulting in increased levels of ROS leading to the further shutdown of redox-sensitive metabolic enzymes and ultimately cell death. As a consequence of these novel properties, thioctoids attack tumor-specific metabolism far more broadly and pervasively than other agents directed at individual metabolic steps or activities. Thioctoids are exceptionally well tolerated in animal studies and as a result may have high clinical potential. They are currently in early stage human clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1122. doi:1538-7445.AM2012-1122