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The review provides an incremental, comprehensive account of topo-active drug resistance mechanisms and evaluates combinatorial approaches using topo-active drugs and pathway inhibitors, supporting interdisciplinary 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\nNilesh Kumar Sharma 1, Anjali Bahot 1, Gopinath Sekar 1, Mahima Bansode 1, Kratika Khunteta 1, Priyanka Vijay Sonar 1, Ameya Hebale 1, Vaishnavi Salokhe 1 and Birandra Kumar Sinha 2, *  \nCitation: Sharma, N.K.; Bahot, A.; Sekar, G.; Bansode, M.; Khunteta, K.; Sonar, P.V.; Hebale, A.; Salokhe, V.; Sinha, B.K. Understanding Cancer’s Defense against TopoisomeraseActive Drugs: A Comprehensive Review. Cancers 2024, 16, 680 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers16040680  \nAcademic Editor: Alexander Shtil  \nReceived: 25 January 2024  \nAccepted: 2 February 2024  \nPublished: 6 February 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Cancer and Translational Research Centre Dr. D.Y. Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, Maharashtra, India; [nilesh.sharma@dpu.edu.in](nilesh.sharma@dpu.edu.in) (N.K.S.);  \n[anjali.bahot@dpu.edu.in](anjali.bahot@dpu.edu.in) (A.B.); [gopinath254867@gmail.com](gopinath254867@gmail.com) (G.S.); [mahima.bansode@dpu.edu.in](mahima.bansode@dpu.edu.in) (M.B.);  \n[20050131@dpu.edu.in](20050131@dpu.edu.in) (K.K.); [21050181@dpu.edu.in](21050181@dpu.edu.in) (P.V.S.); [20050017@dpu.edu.in](20050017@dpu.edu.in) (A.H.);  \n[vaishnavisalokhe1991@gmail.com](vaishnavisalokhe1991@gmail.com) (V.S.)  \n2 Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA  \n* Correspondence: [sinha1@niehs.nih.gov](sinha1@niehs.nih.gov); Tel.: +1-984-287-3382  \nSimple Summary: Increasing number of cancer patients and significant mortality among these patients are attributed to many factors including anticancer drug resistance. Among a pool of available anticancer drugs, topoisomerase-active drugs, e.g., doxorubicin and topotecan are used by cancer patients at high dose and that leads to various side effects and post anticancer therapies complications. Therefore, efforts are warranted to understand the reasons behind such anticancer drug resistance so that better therapeutic management of cancer patients can be achieved. Such efforts could be achieved in the preclinical and clinical laboratory settings so that safer and highly efficacious anticancer drug combinations could be explored for the cancer patients. In the future, combinatorial anticancer drug approaches targeting topoisomerase enzymes can combine newer tools and technologies aided by artificial intelligence and machine learning for rapid and reliable validations of anticancer effects by combinatorial therapeutic approaches.  \nAbstract: 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 u","cbCaikxWAbIXPwth","https://ap.wps.com/l/cbCaikxWAbIXPwth","pdf",3027834,32,"English","# Simple Summary\n# Abstract\n# Keywords\n# Introduction","[{\"question\":\"Why is cancer drug resistance considered a crucial tumor hallmark?\",\"answer\":\"Cancer drug resistance is driven by genetic heterogeneity and intricate cellular complexities, making tumors capable of evading effective therapy over time.\"},{\"question\":\"Which molecular and cellular mechanisms contribute to resistance to topoisomerase-active drugs?\",\"answer\":\"The review highlights oxidative stress, immune evasion, metabolic reprogramming, ABC transporter overexpression, and stemness as key contributing mechanisms.\"},{\"question\":\"What is the purpose of the review regarding topo-active drugs?\",\"answer\":\"It provides an incremental, comprehensive understanding of mechanisms of cancer drug resistance specifically for topo-active drugs and evaluates potential combinatorial strategies using drugs and inhibitors of resistance pathways.\"}]","Understanding Cancer’s Defense against Topoisomerase-Active Drugs - A Comprehensive Review | PDF",1789975931,81]