Investigation in the selective targeting of homologous recombination-deficient cells by benzophenanthridine alkaloid nitidine.

Homologous recombination (HR) plays a crucial role in maintaining genome integrity in mammalian cells. In this study, a natural product screening indicated that the benzophenanthridine alkaloid nitidine chloride (NC) could selectively kill HR-deficient cells. Mechanistically, this selective cytotoxicity of NC results from the induction of double-strand breaks (DSBs) at DNA replication sites because a single-ended DSB is preferentially repaired by HR. Poly ADP ribose polymerase inhibitors, such as olaparib (OLA), have been developed as HR-targeted drugs. Interestingly, NC treatment resulted in cytotoxic effects in OLA-resistant cells, with an NC/OLA combination treatment showing additive effects on cytotoxicity in HR-deficient cells. With its ability to kill HR-deficient cancer cells, NC has potential as a treatment for hereditary breast and ovary cancer syndrome.