Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?

Abstract

DNA topoisomerases are ubiquitously present remarkable molecular machines that help in altering topology of DNA in living cells. The crucial role played by these nucleases during DNA replication, transcription, and recombination vis-à-vis less sequence similarity among different species makes topoisomerases unique and attractive targets for different anticancer and antibacterial drugs. However, druggability of topoisomerases by the existing class of molecules is increasingly becoming questationable due to resistance development predominated by mutations in the corresponding genes. The current scenario facing a decline in the development of new molecules further comprises an important factor that may challenge topoisomerase-targeting therapy. Thus, it is imperative to wisely use the existing inhibitors lest with this rapid rate of losing grip over the target we may not go too far. Furthermore, it is important not only to design new molecules but also to develop new approaches that may avoid obstacles in therapies due to multiple resistance mechanisms. This review provides a succinct account of different classes of topoisomerase inhibitors, focuses on resistance acquired by mutations in topoisomerases, and discusses the various approaches to increase the efficacy of topoisomerase inhibitors. In a later section, we also suggest the possibility of using bisbenzimidazoles along with efflux pump inhibitors for synergistic bactericidal effects.

DNA topoisomerases as molecular targets for anticancer drugs

“…Examples of enzymes belonging to the Top IA subfamily are bacterial topoisomerase I, bacterial topoisomerase III, eukaryotic topoisomerase III and reverse gyrase 1,6,20 .…”

“…The most important example of a type IB topoisomerases is the eukaryotic Top I (including human Top I), which is an important molecular target of anticancer therapies. In addition, Top IB group includes poxvirus topoisomerase and eubacterial Top IB 6,9 .…”

“…They are involved in many significant biological processes in all cells (e.g. DNA replication, transcription and recombination or chromosome condensation) 6 . These enzymes bind covalently to the DNA phosphorus group, split the DNA strand or strands and finally reunite them.…”

Oncofetal HMGA2 attenuates genotoxic damage induced by topoisomerase II target compounds through the regulation of local DNA topology

“…DNA was subjected to electrophoresis in 0.8% agarose gel and stained with ethidium bromide. cells targeted with TOP poisons (Bansal et al, 2017;Ganapathi and Ganapathi, 2013). In this context, our current study uncovered that HMGA2 is a crucial factor that can affect TOP2A function.…”

“…In addition, several tumor‐associated proteins such as YB‐1 (Wu et al , ), p53 (Gobert et al , ) (Kwon et al , ) and ARF (Karayan et al , ) have been shown to enhance TOP activity either through direct protein–protein interactions or by enhancing TOP2 ATPase activity. Such findings could aid in our understanding of cellular chemoresistance that is often observed in cancer cells targeted with TOP poisons (Bansal et al , ; Ganapathi and Ganapathi, ). In this context, our current study uncovered that HMGA2 is a crucial factor that can affect TOP2A function.…”