title: Combined treatment with vitamin C and methotrexate inhibits triple-negative breast cancer cell growth by increasing H2O2 accumulation and activating caspase-3 and p38 pathways.
abstract: Methotrexate (MTX) is widely used as both an anticancer and anti-rheumatoid arthritis drug. Although MTX has been used to inhibit the growth of many cancer cells, it cannot effectively inhibit growth of triple-negative breast cancer cells (TNBC cells). Vitamin C is an antioxidant that can prevent oxidative stress. In addition, vitamin C has been applied as adjunct treatment for growth inhibition of cancer cells. Recent studies indicated that combined treatment with vitamin C and MTX may inhibit MCF-7 and MDA-MB-231 breast cancer cell growth through G2/M elongation. However, the mechanisms remain unknown. The aim of the present study was to determine whether combined treatment with low-dose vitamin C and MTX inhibits TNBC cell growth and to investigate the mechanisms of vitamin C/MTX-induced cytotoxicity. Neither low-dose vitamin C alone nor MTX alone inhibited TNBC cell growth. However, combined low-dose vitamin C and MTX had synergistic anti-proliferative/cytotoxic effects on TNBC cells. In addition, co-treatment increased H2O2 levels and activated both caspase-3 and p38 cell death pathways.
authors.affiliation: Department of Cardiac Surgery, Tungs' Taichung Metroharbor Hospital, Taichung 435, Taiwan, R.O.C.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Wu
authors.affiliation: Department of Nursing, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan, R.O.C.
authors.forename: Hsiao-Chun
authors.initials: HC
authors.lastname: Liu
authors.affiliation: Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Yung-Luen
authors.initials: YL
authors.lastname: Yu
authors.affiliation: Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung 433, Taiwan, R.O.C.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Hung
authors.affiliation: Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung 433, Taiwan, R.O.C.
authors.forename: Chyou-Wei
authors.initials: CW
authors.lastname: Wei
authors.affiliation: Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan, R.O.C.
authors.forename: Giou-Teng
authors.initials: GT
authors.lastname: Yiang
mesh_terms: D001205:Ascorbic Acid / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D008727:Methotrexate / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D006861:Hydrogen Peroxide; C505407:CASP3 protein, human; D053148:Caspase 3; D001205:Ascorbic Acid; D008727:Methotrexate