Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

Abstract

In recent years, the emergence of cancer drug resistance has been one of the crucial tumor hallmarks that are supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters, and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often result in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores the use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.

In silico exploration of anti-prostate cancer compounds from differential expressed genes

“…In cancer therapy, drug combination approach has been found to overcome the problems related to monotherapy and several studies have already demonstrated the superiority of combined therapies compared to monotherapy [ 83 ]. Combinations of small molecular inhibitors against specific DNA repair proteins and cytotoxic drugs have been suggested as future approach to achieve success in cancer treatment [ 84 ]. The identified drugs could have potential interactions with existing PCa treatments.…”

Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases

“…DNA damage-inducing therapies are fundamental in cancer treatment, as evidenced by the crucial roles of chemotherapy and radiotherapy, both of which operate by directly or indirectly inflicting DNA damage ( 89 ). These therapies can alter the DNA nucleotides, induce single-strand (SSBs) or double-strand breaks (DSBs), intercalate between bases, or form crosslinks within DNA or between DNA and proteins ( 90 – 94 ). Additionally, certain compounds induce DNA damage indirectly, e.g., by inhibiting the synthesis of deoxyribonucleotides ( 95 , 96 ).…”