Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin

Tiffany J Tzeng; Lei Cao; YangXin Fu; Huawei Zeng; Wen-Hsing Cheng

doi:10.1371/journal.pone.0101664

Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin

PLoS One. 2014 Jul 10;9(7):e101664. doi: 10.1371/journal.pone.0101664. eCollection 2014.

Authors

Tiffany J Tzeng¹, Lei Cao², YangXin Fu³, Huawei Zeng⁴, Wen-Hsing Cheng⁵

Affiliations

¹ Department of Nutrition and Food Science, University of Maryland, College Park, Maryland, United States of America.
² Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi, United States of America.
³ Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
⁴ USDA, Agriculture Research Service, Grand Forks Human Research Center, Grand Forks, North Dakota, United States of America.
⁵ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcysteine / pharmacology
Antineoplastic Agents / pharmacology*
Ataxia Telangiectasia Mutated Proteins / chemistry
Ataxia Telangiectasia Mutated Proteins / metabolism
Carboplatin / pharmacology*
Cell Cycle / drug effects
Cell Line, Tumor
Chromones / pharmacology
DNA-Binding Proteins / metabolism
Drug Synergism
Female
Gene Expression Regulation, Neoplastic / drug effects
Histones / metabolism
Humans
Morpholines / pharmacology
Organoselenium Compounds / pharmacology*
Ovarian Neoplasms / pathology*
Phosphorylation / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptor, Notch3
Receptors, Notch / metabolism*
Thioxanthenes / pharmacology

Substances

2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide
2-(morpholin-4-yl)benzo(h)chromen-4-one
Antineoplastic Agents
Chromones
DNA-Binding Proteins
H2AX protein, human
Histones
Morpholines
NOTCH3 protein, human
Organoselenium Compounds
RNA, Messenger
Receptor, Notch3
Receptors, Notch
Thioxanthenes
methylselenic acid
Carboplatin
Ataxia Telangiectasia Mutated Proteins
Acetylcysteine

Grants and funding

This study was partially supported by Maryland Agricultural Experimental Station and Mississippi Agricultural and Forestry Experimental Station (to W.-H. Cheng), and by Women and Children's Health Research Institute with funding donated by the Royal Alexandra Hospital Foundation, Canada (to Y. Fu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.