Blackman RK~Nislow C, 2012

Pubmed ID 22253786
Title Mitochondrial electron transport is the cellular target of the oncology drug elesclomol.
Authors Ronald K Blackman, Kahlin Cheung-Ong, Marinella Gebbia, David A Proia, Suqin He, Jane Kepros, Aurelie Jonneaux, Philippe Marchetti, Jerome Kluza, Patricia E Rao, Yumiko Wada, Guri Giaever, Corey Nislow
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.
Citation PLoS ONE 2012; 7:e29798


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Papers Phenotype Conditions Collection Tested mutants Data Details
Blackman RK~Nislow C, 2012 growth (relative abundance in pooled culture) elesclomol [IC15] hom 4,424 Quantitative
Blackman RK~Nislow C, 2012 growth (relative abundance in pooled culture) elesclomol [IC15] het 1,150 Quantitative

Curation history

Sept. 26, 2016 Tested strains to load.
Sept. 26, 2016 Data to load.
Oct. 14, 2016 Data clarification needed.
Oct. 14, 2016 Data requested.
Feb. 24, 2017 Tested strains loaded.
Feb. 24, 2017 Data loaded.