Mitochondrial Electron Transport Is the Cellular Target of the Oncology Drug Elesclomol

Abstract

Elesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. However, the molecular target(s) and mechanism by which elesclomol generates ROS and subsequent cell death were previously undefined. The cellular cytotoxicity of elesclomol in the yeast S. cerevisiae appears to occur by a mechanism similar, if not identical, to that in cancer cells. Accordingly, here we used a powerful and validated technology only available in yeast that provides critical insights into the mechanism of action, targets and processes that are disrupted by drug treatment. Using this approach we show that elesclomol does not work through a specific cellular protein target. Instead, it targets a biologically coherent set of processes occurring in the mitochondrion. Specifically, the results indicate that elesclomol, driven by its redox chemistry, interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and consequently cell death. Additional experiments in melanoma cells involving drug treatments or cells lacking ETC function confirm that the drug works similarly in human cancer cells. This deeper understanding of elesclomol's mode of action has important implications for the therapeutic application of the drug, including providing a rationale for biomarker-based stratification of patients likely to respond in the clinical setting.

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

“…However, if increased mitochondrial ROS could be achieved using alternative means, it could be quite effective in enhancing AML cell killing. To explore this therapeutic strategy, we tested the effects of several drugs known or suspected to cause mitochondrial oxidative stress in leukemia cells, including phenformin and elesclomol (electron transport chain inhibitors) (22,23), tigecycline (inhibitor of mitochondrial translation) (24), and valproic acid (shown to impair ATM levels and induce ROS) (25) for their ability to augment mitochondrial ROS production when combined with FLT3 inhibitor AC220 in Molm13 cells. Elesclomol at nanomolar concentrations was shown to be as effective as ATM or G6PD inhibitors (KU5593 or DHEA) at inducing mitochondrial ROS (Fig.…”

Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants

“…Elesclomol, provided by Synta Pharmaceuticals Corp., was prepared as described (6). The combined effect of dichloroacetate (DCA) and elesclomol was analyzed by the combination index isobologram (22).…”

“…According to this view, elesclomol, a pro-oxidant molecule that targets the mitochondrial electron transport chain (ETC; ref. 6), has been evaluated in clinical trials for the treatment of metastatic melanomas and has shown encouraging clinical responses. Intriguingly, clinical favorable responses occurred in a subset of patients distinguished by low serum lactate dehydrogenase (LDH; ref.…”

“…Thus, serum LDH can be considered as the predictor of response to elesclomol. At a cellular level, elesclomol requires a functioning ETC to induce ROS-mediated melanoma cell death (6). In this context, unraveling the regulatory mechanisms essential for enhancing ROS production is fundamental for improving the efficiency of pro-oxidants in melanoma.…”

Evaluation of the radiosensitizing potency of chemotherapeutic agents in prostate cancer cells

“…The primary mechanism of action of the drug elesclomol [N-malonyl-bis (N 0 -methyl-N 0 -thiobenzoylhydrazide)] is the generation of ROS leading to oxidative stress which induces growth arrest and apoptosis in cancer, but not normal, cells (Kirshner et al 2000;Qu et al 2009;Nagai et al 2012). In preclinical studies, elesclomol sensitized cancer cells to other chemotherapeutic agents (Qu et al 2009;Blackman et al 2012) and, when combined with paclitaxel in a phase II clinical trial, was shown to prolong progressionfree survival in patients with metastatic melanoma (O'Day et al 2009). Therefore, drug-induced increase in ROS is a potentially effective method to enhance the efficacy of radiotherapy.…”