title: Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin.
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.
authors.affiliation: Department of Nutrition and Food Science, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Tiffany J
authors.initials: TJ
authors.lastname: Tzeng
authors.affiliation: Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: YangXin
authors.initials: Y
authors.lastname: Fu
authors.affiliation: USDA, Agriculture Research Service, Grand Forks Human Research Center, Grand Forks, North Dakota, United States of America.
authors.forename: Huawei
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Nutrition and Food Science, University of Maryland, College Park, Maryland, United States of America; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi, United States of America.
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Cheng
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000737:chemistry / Q000378:metabolism; D016190:Carboplatin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D013892:Thioxanthenes / Q000494:pharmacology
chemical_list: C546193:2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide; C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; D000970:Antineoplastic Agents; D002867:Chromones; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D009025:Morpholines; C499374:NOTCH3 protein, human; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D013892:Thioxanthenes; C008493:methylselenic acid; D016190:Carboplatin; D064007:Ataxia Telangiectasia Mutated Proteins; D000111:Acetylcysteine