Quercetin exhibits cytotoxicity in cancer cells by inducing two-ended DNA double-strand breaks

Quercetin, a flavonoid, is involved in the induction of DNA double-strand breaks (DSBs), in addition to its antioxidant properties. Although DNA topoisomerase II (Top2) and reactive oxygen species (ROS) have been suggested as possible mechanisms through which quercetin induces DSBs, the exact mechanism remains unclear. In this study, we examined the mechanism of DSB induction by quercetin and its repair using HeLa cells and gene-knockout cell lines generated from human Nalm-6 cells. Immunofluorescence staining for γH2AX, a DSB marker, and analysis of the frequency of random integration of foreign DNA, which correlates with the number of DSBs and DSB repair pathways, indicated that quercetin induces DSBs in a concentration-dependent manner. The sensitivity assay suggested that the factor involved in quercetin-induced DSBs was not Top2. However, ROS was found to accumulate transiently in quercetin-treated HeLa cells. Furthermore, the addition of ascorbic acid increased the survival of quercetin-treated HeLa cells, suggesting that quercetin induces a transient accumulation of ROS, which in turn induces DSBs. The resulting DSBs were repaired primarily by non-homologous end-joining and homologous recombination, similar to X-ray-induced DSBs. Taken together, quercetin, used as a radiomimetic agent, has the potential to produce effects equivalent to those of an X ray-dose at a relatively low risk.