Flavonoids: Novel topoisomerase inhibitors in cancer therapy

Cancer continues to represent one of the most alarming global public health challenges, with its burden rising across both developed and developing nations. Therefore, it is essential to address this increasing global prevalence of cancer for prevention and proper cancer management which will help to reduce the cancer burden and the death caused by it. Natural compounds have gained increasing attention as potential anticancer agents due to their structural diversity, bioavailability, and comparatively lower toxicity. Among these, flavonoids, naturally occurring secondary metabolites of plants belonging to the polyphenolic class have been extensively reported to exhibit a broad spectrum of pharmacological properties, including notable anticancer activity. Human DNA topoisomerases (Topo), essential nuclear enzymes responsible for maintaining DNA topology during replication, transcription, recombination, and repair, have emerged as well-established and clinically validated targets in anticancer therapy. Several chemotherapeutic agents function by targeting these enzymes; however, their clinical application is often limited by severe toxicity and the development of drug resistance. So, this review comprehensively summarizes naturally occurring flavonoids with demonstrated anticancer potential, with a particular focus on their ability to target and modulate the activity of human DNA topoisomerases. By integrating available biochemical, cellular, and molecular evidence, this article provides critical insights into flavonoid-topoisomerase interactions and their role in cancer inhibition. The information presented herein may serve as a valuable foundation for the rational design and development of novel, flavonoid-based topoisomerase inhibitors, offering a promising alternative approach for next-generation anticancer drug discovery.