title: Triethylenetetramine Synergizes with Pharmacologic Ascorbic Acid in Hydrogen Peroxide Mediated Selective Toxicity to Breast Cancer Cell.
abstract: Breast cancer is characterized by overexpression of superoxide dismutase (SOD) and downregulation of catalase and more resistance to hydrogen peroxide (H2O2) than normal cells. Thus, relatively high H2O2promotes breast cancer cell growth and proliferation. However, excessive intracellular H2O2leads to death of breast cancer cells. In cancer cells, high level ascorbic acid (Asc) is able to be autoxidized and thus provides an electron to oxygen to generate H2O2. In the present study, we demonstrated that triethylenetetramine (TETA) enhances Asc autoxidation and thus elevates H2O2production in MCF-7 cells. Furthermore, Asc/TETA combination significantly impaired cancer cell viability, while having much milder effects on normal cells, indicating Asc/TETA could be a promising therapy for breast cancer. Moreover, SOD1 and N-acetyl-L-cysteine failed to improve MCF-7 cells viability in the presence of Asc/TETA, while catalase significantly inhibited the cytotoxicity of Asc/TETA to breast cancer cells, strongly suggesting that the selective cytotoxicity of Asc/TETA to cancer cells is H2O2-dependent. In addition, Asc/TETA induces RAS/ERK downregulation in breast cancer cells. Animal studies confirmed that Asc/TETA effectively suppressed tumor growth in vivo. In conclusion, TETA synergizes pharmacologic Asc autoxidation and H2O2overproduction in breast cancer cells, which suppresses RAS/ERK pathway and results in apoptosis.
authors.affiliation: Department of Reproduction Health and Infertility, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Lianlian
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Li
authors.affiliation: Molecular Medicine and Cancer Research Center, Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yubing
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: College of Medicine, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Laetitia H
authors.initials: LH
authors.lastname: Lloyd-Davies
authors.affiliation: Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Delplancke
authors.affiliation: Laboratory of Lipid & Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Peng
authors.affiliation: Laboratory of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Rufei
authors.identifier: 0000-0002-8437-9630
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Chao
authors.identifier: 0000-0003-0828-2674
authors.initials: C
authors.lastname: Tong
authors.affiliation: Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; College of Medicine, University of Leicester, Leicester LE1 7RH, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Baker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D061986:MCF-7 Cells; D051379:Mice; D010084:Oxidation-Reduction; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014266:Trientine / Q000494:pharmacology*
chemical_list: D013481:Superoxides; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D048049:Extracellular Signal-Regulated MAP Kinases; D001205:Ascorbic Acid; D014266:Trientine