Mechanism studies of thiosemicarbazone inhibition on human topoisomerase IIα

Abstract

Proteins possess a high diversity of functions within cells which can be regulated by small molecule binding. The protein topoisomerase II within humans is responsible for the higher order structural regulation of DNA and has been the target of small molecule anti-cancer therapies including thiosemicarbazones such as etoposide, a commercially available interfacial poison of topoisomerase II. However, these therapies present significant, detrimental side effects thought to be imposed by the inhibition of both isoforms, alpha and beta, found throughout the body. Indeed, significant evidence suggests inhibition of the mitotic-associated alpha isoform negatively regulates cancer cell proliferation while inhibition of the interphase-associated beta isoform is the cause of side effects. By selectively targeting the alpha isoform with novel metal-ligand complexes of thiosemicarbazones a therapy which retains efficacy but disposes of undesired effects is hoped to be achieved. Presented is a series of DNA assays of varying concentrations of thiosemicarbazone complexes.