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Methylseleninic acid sensitizes Notch3 activated ovarian cancer cells to carboplatin

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, ovarian cancer eventually develops resistance to this platinum‐containing drug. Animal studies have demonstrated efficacies of methylseleninic acid (MSeA) in counteracting tumorigenesis. Expression of Notch3 is associated with chemoresistance and correlated with poor overall survival of human ovarian cancer patients. Here we tested the hypothesis that MSeA can sensitize OVCA429/NICD3 cells to carboplatin treatment. Overexpression of NICD3 (the constitutively active form of Notch3) in OVCA429 ovarian cancer cells (OVCA429/NICD3) rendered them resistance to carboplatin compared to OVCA429 cells transduced with an empty vector (OVCA429/pCEG). Co‐treatment with MSeA sensitized OVCA429/NICD3, but not OVCA429/pCEG cells to carboplatin treatment. These two chemicals appear to synergistically kill OVCA429/NICD3 cells, which can be suppressed by the presence of N‐acetyl cysteine or DNA damage kinase inhibitors of ATM and DNA‐PKcs. In summary, MSeA sensitizes OVCA429/NICD3 cells to carboplatin treatment in a pathway involves oxidative stress, ATM and DNA‐PKcs, suggesting a new strategy to improve the efficacy of carboplatin treatment against ovarian cancer.