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.
Keywords: Apoptosis, Cancer, Caspases, Chromosomal decatenation, Cysteine-aspartic proteases, DNA topology, Topoisomerases.
