Targeting topoisomerase I: molecular mechanisms and cellular determinants of response to topoisomerase I inhibitors

Abstract

Background : Topoisomerase I is required for DNA relaxation during critical cellular functions. The identification of camptothecins as specific enzyme inhibitors and their clinical efficacy have stimulated extensive efforts to exploit topoisomerase I as a tumor target and explain the putative mechanisms of antitumor-specific action. Objective : This review provides an overview of the recent achievements in the development of topoisomerase I inhibitors and in the explanation of the biological pathways involved in tumor response. Results/conclusion : In spite of the difficulty to identify novel topoisomerase I inhibitors with improved pharmacological properties, a growing body of evidence supports the possibility of optimizing the therapeutic profile of available agents. The explanation of defense mechanisms and the molecular determinants of tumor cell response is expected to provide a basis for the design of combination approaches for optimization of topoisomerase I inhibitors-based therapy.

Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid

“…These enzymes have been identified as important targets in cancer chemotherapy and microbial infections (Kumar Singh et al 2007). In fact, topoisomerase I inhibitors are quoted as having a wide range of antitumor activities and are among the most widely used anticancer drugs clinically (Sunami et al 2009;Rothenberg 1997;Beretta et al 2008;Teicher 2008;Pommier 2008). However, not many metal complexes have been reported to inhibit topoisomerases.…”

Structure–Activity Relationship Study of 16 a‐Thiocamptothecins: an Integrated In Vitro and In Silico Approach

“…The design of novel analogues is aimed at overcoming the primary limitations of conventional CPTs, including lactone instability, reversibility of drug-target interactions and drug resistance. [25,28] Recent evidence supports to hypothesis that lipophilicity may confer potential advantages to CPTs in terms of cytotoxic potency, likely related to favorable cellular pharmacokinetics, and lactone stability. [29] Among these efforts, we previously reported the potential interest of 16 a-thiocamptothecin.…”

Synthesis, characterization and biological properties of cobalt(II) complexes of 1,10-phenanthroline and maltol

“…These topoisomerases are important in DNA replication and transcription. Topo I inhibitors have been reported to be among the most widely used clinical drugs for treatment of cancer [55][56][57][58][59]. Gel electrophoresis can be used to view the topoisomers which result from relaxation of supercoiled pBR322 by Topo I [60].…”