Flavonoids as Dual Topoisomerase I and II Inhibitors: Mechanistic Insights and Emerging Anticancer Strategies

Flavonoids, a diverse class of plant-derived polyphenolic compounds found in fruits, vegetables, and medicinal herbs, have gained considerable attention for their chemopreventive and anticancer properties. A key mechanism underlying their therapeutic potential is the modulation of DNA topoisomerases, enzymes essential for DNA replication, transcription, and recombination. Inhibition of topoisomerase I and II induces DNA damage, replication stress, and apoptosis in rapidly proliferating cancer cells. Flavonoids such as quercetin, kaempferol, myricetin, and epigallocatechin-3-gallate (EGCG) act as topoisomerase poisons or catalytic inhibitors by stabilizing the enzyme-DNA cleavage complex, leading to DNA strand breaks. Additionally, their pro-oxidant properties can enhance reactive oxygen species (ROS) generation, further amplifying DNA damage in tumor cells. Structural modifications of flavonoid scaffolds have improved enzyme selectivity, cellular uptake, and anticancer efficacy across various cancers, including leukemia, breast, colon, and lung cancer. Preclinical studies also highlight their synergistic potential with conventional chemotherapeutics, contributing to reduced drug resistance and toxicity. However, challenges such as poor bioavailability and metabolic instability remain. Advances in nanocarrier-based delivery and targeted therapeutic strategies may enhance their clinical translation as promising anticancer agents.