Nicaraven enhances the cytotoxicity of X-ray irradiation in cancer cells with homologous recombination deficiency.

Abstract

Poly (ADP-ribose) polymerase (PARP) is involved in the repair of DNA single-strand breaks. PARP inhibitors are cytotoxic to cancer cells with homologous recombination (HR) deficiency through a synthetic lethality mechanism. Nicaraven is a hydroxyl radical scavenger that has been investigated for the treatment of organ ischemia such as brain infarction. Nicaraven also shows PARP inhibitory and anti-cancer activity in vitro and in vivo. In this study, we investigated the potential synthetic lethality of nicaraven in cells with HR deficiency and whether the PARP inhibitory and radical scavenger activities of nicaraven contributes to its anti-cancer effects, especially in combination with exposure to ionizing radiation. The results showed that nicaraven was cytotoxic against cancer cells after knockdown of the HR factors BRCA1 or RAD51, indicating that nicaraven exerted synthetic lethal effects on cells with HR deficiency. X-ray irradiation-induced DNA double-strand breaks (DSBs) increased at 2 h and were largely repaired after 24 h in control cells, whereas nicaraven significantly increased the amounts of residual DSBs 24 h after X-ray irradiation, especially in HR-deficient cells. Nicaraven treatment enhanced the cytotoxicity of X-ray irradiation in HR-deficient cells, but not that in HR-proficient cells. These data suggest that the combination of nicaraven with X-ray irradiation selectively increases the cytotoxic effects of X-ray irradiation on HR-deficient cancer cells. Thus, nicaraven might be a valuable agent for cancer therapy, particularly in combination with radiotherapy.