Ovarian cancer, the deadliest of gynecologic
cancers, is usually not diagnosed until advanced stages. Although
carboplatin has been popular for treating
ovarian cancer for decades, patients eventually develop resistance to this
platinum-containing
drug. Expression of neurogenic locus notch homolog 3 (Notch3) is associated with chemoresistance and poor overall survival in
ovarian cancer patients. Overexpression of NICD3 (the constitutively active form of Notch3) in OVCA429
ovarian cancer cells (OVCA429/NICD3) renders them resistance to
carboplatin treatment compared to OVCA429/pCEG cells expressing an empty vector. We have previously shown that
methylseleninic acid (MSeA) induces oxidative stress and activates
ataxia-telangiectasia mutated and
DNA-dependent protein kinase in
cancer cells. Here we tested the hypothesis that MSeA and
carboplatin exerted a synthetic lethal effect on OVCA429/NICD3 cells. Co-treatment with MSeA synergistically sensitized OVCA429/NICD3 but not OVCA429/pCEG cells to the killing by
carboplatin. This synergism was associated with a cell cycle exit at the G2/M phase and the induction of NICD3 target gene HES1. Treatment of N-acetyl
cysteine or inhibitors of the above two
kinases did not directly impact on the synergism in OVCA429/NICD3 cells. Taken together, these results suggest that the efficacy of
carboplatin in the treatment of high grade ovarian
carcinoma can be enhanced by a combinational
therapy with MSeA.