Methylseleninic Acid Sensitizes Notch 3-activated OVCA429 Ovarian Cancer Cells to Carboplatin

Abstract

Ovarian cancer is the deadliest of gynecologic cancers and is usually diagnosed at advanced stage due to invalidated screening test. Although carboplatin has been used for treating ovarian cancer for years, high-grade serous ovarian cancer expressing a constitutively active form of the intracellular domain of Notch 3 develops resistance to this platinum-containing drug. Thus, finding a novel treatment or therapeutic targets are necessary. Here we test the hypothesis that the combinational treatment of methylseleninic acid (MSeA) and carboplatin, two chemicals displaying overlapping effect on DNA damage response, may target Notch 3 for improved efficacy on ovarian cancer treatment. The OVCA429/NICD3 cells expressing an activated form of Notch 3 were resistant to carboplatin, but co-treatment with MSeA synergistically sensitized the cell to an extent similar of that in OVCA429/pCEG control cells. The synergistic effect can be suppressed by the presence of a hydrogen peroxide scavenger N-acetyl cysteine (NAC) and kinase inhibitors of ATM and DNA-PKcs. In summary, MSeA and carboplatin synergistically sensitize OVCA429/NICD3 cells in a pathway involves oxidative stress, ATM and DNA-PKcs, suggesting a new strategy to improve the efficacy of carboplatin treatment for high-grade ovarian cancer.