Abstract 1757: Elesclomol (STA-4783) is a potent inhibitor of topoisomerase II

Abstract

Abstract Elesclomol (STA-4783; N’1, N’3-dimethyl-N’1, N’3- bis(phenylcarbonothioyl)propanedihydrazide) 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 copper(II) and may exert its anticancer activity through the induction of oxidative stress. In the studies reported here elesclomol was assessed for its ability to inhibit: 1) the growth of the human erythroleukemic K562 cell line and an etoposide-resistant K/VP.5 cell line; 2) the decatenation activity of DNA topoisomerase IIα; and 3) the relaxation activity of DNA topoisomerase I. Elesclomol was also evaluated for its ability to induce topoisomerase IIα-mediated double strand cleavage of pBR322 DNA and to form topoisomerase IIα-DNA covalent adducts in the cell-based ICE assay. Elesclomol inhibited K562 cell growth in the submicromolar concentration range. However, K/VP.5 cells were not cross-resistant. Elesclomol also strongly inhibited the decatenation activity of topoisomerase IIα in the low micromolar concentration range. Elesclomol may also act as topoisomerase IIα poison because it induced formation of linear DNA, though not as strongly as etoposide. In conclusion, these results show that elesclomol may, in part, inhibit cell growth through the targeting of topoisomerase II. Support: CIHR, a Canada Research Chair in Drug Development to B.B.H., a National Institutes of Health grant CA090787 to J.C.Y. 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 1757. doi:1538-7445.AM2012-1757