The Anticancer Agent Elesclomol Has Direct Effects on Mitochondrial Bioenergetic Function in Isolated Mammalian Mitochondria

Abstract

Elesclomol ((N-malonyl-bis(N'-methyl-N'-thiobenzoylhydrazide)); formerly STA-4783) is a mitochondria-targeted chemotherapeutic agent that has demonstrated efficacy in selective cancer cell killing in pre-clinical and clinical testing. The biologically active form of elesclomol is a deprotonated copper chelate (elesclomol:copper; E:C), which has been shown to enhance reactive oxygen species (ROS) production and induce a transcriptional gene profile characteristic of an oxidative stress response in vitro. Previous studies suggest that E:C interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and ultimately induce cell death. The purpose of this study was to further explore the mechanism of cellular and mitochondrial toxicity of E:C by examining its direct effect on mitochondrial bioenergetic function. The results obtained indicate that E:C treatment in whole cells of non-tumorigenic origin at high concentrations (40 M and higher) induces a rapid and substantial increase in mitochondrial superoxide levels and dissipation of mitochondrial membrane potential. Furthermore, similar higher concentrations of E:C act as a direct uncoupler of oxidative phosphorylation and generalized inhibitor of electron transport activity in isolated, intact mitochondria, and induce a dose-dependent inhibition of mitochondrial NADH-ubiquinone oxidoreductase activity in freeze-thawed mitochondrial preparations. The results of this study are important in that they are the first to demonstrate a direct effect of the E:C chelate on bioenergetic function in isolated mammalian mitochondria, and suggest the possibility that the increase in ROS production and cytotoxicity induced by E:C may in part be due to uncoupling of mitochondrial oxidative phosphorylation and/or inhibition of electron transport activity. These results also provide important information about the mechanisms of mitochondrial and cellular toxicity induced by E:C and will ultimately contribute to a better understanding of the therapeutic potential of elesclomol as an anticancer compound.

Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

“…3B and C, respectively), although the latter appeared slightly less sensitive to the drug. This agrees perfectly with what is reported by Modica-Napolitano and collaborators who identified the electron transport chain as a selective target of elesclomol [43]. Indeed, cytoplasmic ROS (i.e., by using also Hydroethidine and H 2 DCFDA, data not shown) increased significantly less markedly than mitochondrial ROS, thus indicating that mitochondrial stress may represent the primum movens of the elesclomol toxicity.…”

Potential biomarkers and targets of mitochondrial dynamics

“… 134 SS‐31 as a mitochondria‐targeted therapeutic agent binds to cardiolipin on the inner mitochondrial membrane and protects the electron carrying function of cytochrome C. 135 Elesclomol as a mitochondria‐targeted chemotherapeutic compound has the anticancer efficacy in preclinical and clinical testing. 136 On the other hand, the mitochondrial signal‐retaining autophagy indicator with acid‐fast fluorescent protein tags (TOLLES: tolerance of lysosomal environment) and Ypet are applied to visualize mitophagy. Since TOLLES and Ypet are effectively degraded by mitophagy, their molecular linkage is quantifiable as a new mitophagy indicator for high‐throughput screening of therapeutic mitophagy inducers to target damaged mitochondria.…”

Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells, a Model of VPS13-Related Diseases

“…Disulfiram improved cytochrome c oxidase activity in models of Menkes disease [70] and was also shown to rescue respiratory growth defects related to copper deficiency in yeast [71]. The next tested copper ionophore, which we selected after performing the screen, was elesclomol ( Figure 5), an anticancer candidate drug [72][73][74][75][76][77][78] that increases intracellular copper content with high selectivity to mitochondria [79,80] and targets electron transport chain [81,82]. It was also shown to rescue defects observed in various copper deficiency models, including Menkes disease model [80,83].…”