title: Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of clonogenic resistance in breast cancer cells by combined cisplatin and FK228.
abstract: Safe and effective combination chemotherapy regimens against breast cancer are lacking. We used our cellular system, consisting of the non-cancerous human breast epithelial MCF10A cell line and its derived tumorigenic, oncogenic H-Ras-expressing, MCF10A-Ras cell line, to investigate the effectiveness of a combination chemotherapy regimen in treating breast cancer cells using two FDA-approved agents, cisplatin and FK228. Cisplatin and FK228 significantly, synergistically, and preferentially induced death and reduced drug resistance of MCF10A-Ras versus MCF10A cells. The ERK-Nox-ROS pathway played a major role in both synergistic cell death induction and GSH-level reduction, which contributed to the synergistic suppression of drug resistance in cells. Enhancement of the Ras-ERK-Nox pathway by combined cisplatin and FK228 significantly increased ROS levels, leading to induction of death, reduction of drug resistance, and induction of DNA damage and oxidation in cancerous MCF10A-Ras cells. Furthermore, synergistic induction of cell death and reduction of drug resistance by combined cisplatin and FK228 in breast cells is independent of their estrogen receptor status. Our study suggests that combined cisplatin and FK228 should be considered in clinical trials as a new regimen for therapeutic control of breast cancers.
authors.affiliation: Anticancer Molecular Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA.
authors.forename: Lenora Ann
authors.initials: LA
authors.lastname: Pluchino
authors.affiliation: Anticancer Molecular Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA.
authors.forename: Shambhunath
authors.initials: S
authors.lastname: Choudhary
authors.affiliation: Anticancer Molecular Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA. Electronic address: hcrwang@utk.edu.
authors.forename: Hwa-Chain Robert
authors.initials: HC
authors.lastname: Wang
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D047630:Depsipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D047630:Depsipeptides; D017382:Reactive Oxygen Species; C087123:romidepsin; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D002945:Cisplatin
keywords: Breast cancer; Cisplatin; ERK pathway; FK228; Reactive oxygen species