Human Topoisomerases and Caspases: Important Targets in Cancer Therapy

Abstract

Cancer has always remained a major challenge to humanity with its rising morbidity and mortality rate making it uncontrollable. Current treatments for cancer offer limited efficacy and suffer from serious side effects. With a focus on making treatment safer and more effective, there is a need to identify novel targets and potent drugs for these targets. Recent years have witnessed significant progress in the discovery of targeted cancer therapy. On-going research in this field suggests that human topoisomerases and caspases are important molecular drug targets for anti-cancer drug development. Topoisomerases are DNA processing enzymes essentially required to maintain DNA topology during transcription, replication, recombination and chromosomal decatenation. Several new chemical classes of topoisomerase inhibitors including natural product derivatives are in clinical trials for the treatment of various human cancers. Several topoisomerase inhibitors such as topotecan, irinotecan, camptothecin, teniposide and doxorubicin are clinically approved for various cancers such as colon cancer, lung cancer, breast cancer, and many more. However, many of these inhibitors have also been associated with serious side effects during chemotherapy. Emerging data in recent years also suggests the role of topoisomerase inhibition in immunogenic cell death and activating anticancer immune responses making them potential combinatorial modalities for cancer immunotherapy. Caspases [1-12] belong to the family of cysteine-aspartic proteases responsible for the execution of cell death in apoptotic cells. Caspases play an important role in various non-lethal biological processes like cell proliferation, cell differentiation, intercellular communication, and cell migration. The dysregulation of apoptotic signalling pathways is considered one of the hallmarks of cancer. Hence the focus of cancer therapy is correcting this aberrant behaviour. Natural products such as alkaloids, flavonoids, diterpenoids, sesquiterpenes, and polyphenolics have been reported with various anticancer properties. In this chapter, we have discussed topoisomerases and the regulation of caspase functions through direct or indirect methods for anticancer drug discovery.