Abstract 5559: Molecular mechanisms of elesclomol cytotoxicity.

Abstract

Abstract Elesclomol is an anticancer drug that has received both fast track and orphan drug status from the FDA and is currently undergoing clinical trials. Elesclomol forms a strong 1:1 complex with Cu2+ and may exert its anticancer activity through the induction of oxidative stress or its ability to transport Cu2+ into the cell. The complexes of elesclomol with redox inactive Pt2+ and Ni2+ were much less cytotoxic than its Cu2+ complex which suggests a role for Cu2+-induced oxidative stress. Elesclomol and Cu2+-elesclomol inhibited the growth of human erythroleukemic K562 cells in the low nanomolar concentrations with even a brief 1.5 hr exposure. The cell growth inhibitory effects of elesclomol were decreased with an increase in cell density, likely due to Cu2+ depletion of the medium. Consistent with this, the addition of the Cu2+ chelator Trien to the medium decreased cytotoxicity. Cu2+-elesclomol induced caspase 3/7 in K562 cells, indicating it was apoptosis inducing. The Cu2+-elesclomol complex inhibited topoisomerase I activity and induced topoisomerase I-covalent complexes in K562 cells at a relatively high concentration of 50 μM. It did not, however, inhibit or poison topoisomerase II or produce topoisomerase II-covalent complexes in cells. Cu2+-elesclomol, but not elesclomol, was able to induce γH2AX formation in K562 cells, indicative of DNA double strand breaks. Ascorbic acid, GSH and NADH were all able to slowly reduce the Cu2+-elesclomol complex. However, EPR spin trapping experiments, either in the presence or absence of added H2O2, showed that the reduced copper complex could not directly generate damaging hydroxyl radicals. Depletion of GSH in K562 cells by treatment with BSO sensitized cells to elesclomol and its copper complex, indicating oxidative stress may be responsible for cytotoxicity. In conclusion, these results show that elesclomol may inhibit cell growth through Cu2+-mediated oxidative stress. Support: CIHR, a Canada Research Chair in Drug Development to B.B.H., and a National Institutes of Health grant CA090787 to J.C.Y. Citation Format: Brian B. Hasinoff, Jack C. Yalowich, Daywin Patel, Aron Yadav, Xing Wu. Molecular mechanisms of elesclomol cytotoxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5559. doi:10.1158/1538-7445.AM2013-5559