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.
近年来，癌症耐药性的出现已成为肿瘤关键特征之一，其形成受到遗传异质性水平和细胞层面复杂性的共同影响。氧化应激、免疫逃逸、代谢重编程、ABC转运蛋白过表达以及干细胞特性是其中几个关键的分子与细胞响应机制。拓扑异构酶活性药物（如多柔比星和拓扑替康）在临床上具有活性，被广泛用于治疗多种人类肿瘤，但常导致耐药性产生和治疗失败。因此，亟需在拓扑异构酶活性药物背景下，对癌症耐药机制进行深入而全面的理解。本综述深入探讨了这些细胞内与细胞外拓扑异构酶活性药物耐药机制的复杂机理，并探索了通过联合使用多种拓扑异构酶活性药物及耐药相关通路抑制剂的可能性。我们相信，本综述将有助于引导基础科学家、临床前研究者、临床医生及政策制定者制定跨学科的整体策略，以克服耐药性问题，为持续的抗癌斗争注入新的希望。
Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review
肿瘤(癌症)患者之家