https://doi.org/10.1371/journal.pone.0101664

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College of Agriculture & Life Sciences Publications and Scholarship

Abstract

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.

Publisher

Public Library of Science

Publication Date

7-10-2014

College

College of Agriculture and Life Sciences

Department

Department of Food Science, Nutrition and Health Promotion

Keywords

Acetylcysteine, Acetylcysteine: pharmacology, Antineoplastic Agents, Antineoplastic Agents: pharmacology, Ataxia Telangiectasia Mutated Proteins, Ataxia Telangiectasia Mutated Proteins: chemistry, Ataxia Telangiectasia Mutated Proteins: metabolism, Carboplatin, Carboplatin: pharmacology, Cell Cycle, Cell Cycle: drug effects, Cell Line, Chromones, Chromones: pharmacology, DNA-Binding Proteins, DNA-Binding Proteins: metabolism, Drug Synergism, Female, Gene Expression Regulation, Histones, Histones: metabolism, Humans, Messenger, Messenger: genetics, Messenger: metabolism, Morpholines, Morpholines: pharmacology, Neoplastic, Neoplastic: drug effec, Notch, Notch: metabolism, Organoselenium Compounds, Organoselenium Compounds: pharmacology, Ovarian Neoplasms, Ovarian Neoplasms: pathology, Phosphorylation, Phosphorylation: drug effects, Receptors, RNA, Thioxanthenes, Thioxanthenes: pharmacology, Tumor

Disciplines

Medical Cell Biology | Oncology

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