Abstract
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.
Highlights
Ovarian cancer is one of the most common causes of death among women with gynecologic malignancies
Received 08.6.17; revised 02.8.17; accepted 04.8.17; Edited by R Aqeilan promote the generation of reactive oxygen species (ROS)[21,22] and induce DNA damage in human cancer cells.[6]
We previously reported that berberine could radiosensitize human esophageal cancer cells by downregulating RAD51.14 We measured RAD51 protein level in ovarian cancer cells treated with berberine
Summary
Ovarian cancer is one of the most common causes of death among women with gynecologic malignancies. About 60 − 70% patients with ovarian cancer were diagnosed in their advanced stage and overall 5-year survival is ~ 30%.1. Berberine has been shown to suppress tumor growth in xenograft models.[9,10,11,12,13] Among others, induction of oxidative stress and DNA damage have been reported to mediate apoptosis and cell cycle arrest.[6,8] In addition to acting as a genotoxicant, berberine can radiosensitize cancer cells by downregulating RAD51, a key factor in homologous recombination repair (HRR).[14]. We tested the effect of combined application of berberine and PARP inhibitor on ovarian cancer cells. Our findings may bear implications in designing cancer therapy strategies involving two or more drugs
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