DNA Topoisomerases: As target for anti-cancer drugs

Abstract

Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymes I and II. Topoisomerases are enzymes that control the changes in DNA tridimensional structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. DNA Topoisomerases control the conformational changes in DNA topology by breaking and resealing DNA strands during normal cellular growth, that’s why these are essential enzymes. A major class of anticancer drugs acts as inhibitors of DNA Topoisomerases. This paper gives a brief review on Topoisomerase targeting drugs which shows anticancer activities. The mechanism of action of these drugs by inhibiting type I and type II DNA Topoisomerases are discussed. DNA topoisomerases, especially type II A topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase–drug–DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. It may also be possible to design catalytic inhibitors of topoisomerases by targeting certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.