Berberine induces oxidative DNA damage and impairs homologous recombination repair in ovarian cancer cells to confer increased sensitivity to PARP inhibition

Many cancer drugs exert their therapeutic effect by inducing oxidative stress in the cancer cells. Oxidative stress compromises cell survival by inflicting lesions in macromolecules like DNA. Cancer cells rely on enhanced antioxidant metabolism and increased DNA repair function to survive oxidative assault. PARP1, a protein that senses DNA-strand breaks and orchestrates their repair, has an important role in the repair of oxidative DNA damage. Berberine, an alkaloid compound present in many herbal plants, is capable of inducing oxidative DNA damage and downregulating homologous recombination repair (HRR) in cancer cells. In this study, we demonstrated that berberine and PARP inhibitor niraparib have a synthetic lethal effect on ovarian cancer cells. Oxidative DNA damage was greatly induced by berberine in ovarian cancer cells. In addition, the level of RAD51 and the capacity of HRR were also reduced by berberine. Correspondingly, PARP became hyperactivated in response to berberine treatment. Cancer cells treated with berberine and niraparib in combination exhibited greatly increased apoptosis and remarkably reduced tumor growth in vivo. Together, the results indicate that by inducing oxidative DNA damage and downregulating HRR in cancer cells berberine is able to further sensitize cancer cells to PARP inhibition. Our findings demonstrate a potential therapeutic value of combined application of berberine and PARP inhibitors in ovarian cancer treatment.