Targeting DNA topoisomerase II in Cancer: mechanism of inhibition, clinical utility, and future directions.

Topoisomerase II (TOP2) inhibitors are among the most important classes of anticancer agents owing to their ability to disrupt DNA topology during replication and transcription. Clinically important TOP2-targeted drugs, including etoposide, doxorubicin, and mitoxantrone, have demonstrated substantial efficacy against a broad range of malignancies, including leukemias, lymphomas, and solid tumors such as breast, lung, ovarian, and testicular cancers. These agents exert their antitumor activity by interfering with the TOP2 catalytic cycle, resulting in DNA damage and subsequent cell death. However, their clinical utility is frequently limited by acquired drug resistance, dose-limiting toxicities, and therapy-related secondary malignancies. This review summarizes current advances in the understanding of TOP2 biology, mechanisms of action of TOP2 poisons and catalytic inhibitors, resistance pathways, and therapeutic applications. Particular emphasis is placed on the distinct biological roles of the TOP2A and TOP2B isoforms and their implications for efficacy and toxicity. Recent progress in structure-based drug design, biomarker-guided precision medicine, innovative drug delivery systems, and rational combination strategies is also discussed. Emerging approaches, including isoform-selective inhibitors and targeted protein degradation technologies, offer promising opportunities for improving therapeutic selectivity while reducing adverse effects. These advances support the continued development of safer and more effective TOP2-directed therapies for personalized cancer treatment.