title: Metalloporphyrin synergizes with ascorbic acid to inhibit cancer cell growth through fenton chemistry.
abstract: Ascorbic acid (AA) has been reported to inhibit tumor cell growth through the generation of extracellular hydrogen peroxide (H(2)O(2)). However, the clinical utility of AA has been limited by relatively low potency and in vivo efficacy. This study reports that the metalloporphyrin, Mn(III) tetrakis(N-methylpyridinium-2-yl)porphyrin(5+) (MnTMPyP), has a potent synergistic cytotoxic effect when combined with AA in a variety of cancer cell lines. In the presence of MnTMPyP, the concentration of AA required to inhibit cancer cell growth was markedly reduced. In vitro (cell-free) experiments demonstrated that AA alone enhanced the Fenton reaction that produces cytotoxic hydroxyl radical (HO(*)); however, this reaction was limited by the low rate by which AA generates H(2)O(2) (Fenton reaction substrate) from O(2). MnTMPyP catalyzed H(2)O(2) generation through the AA-facilitated Mn(II <--> III)TMPyP redox cycle and thereby markedly potentiated the Fenton reaction. Accordingly, MnTMPyP and AA resulted in increased cellular levels of H(2)O(2) and HO(*) in cancer cells, which mediate the synergistic cytotoxicity of this combined treatment. This effect was inhibited by cellular enzymes that metabolize H(2)O(2), such as catalase and glutathione peroxidase, suggesting that selective killing of cancer cells deficient in such enzymes can be achieved in vivo.
authors.affiliation: Department of Radiation Oncology, Stanford University, California 94305-5152, USA.
authors.forename: Junqiang
authors.initials: J
authors.lastname: Tian
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peehl
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Knox
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D001205:Ascorbic Acid / Q000494:pharmacology*; D015153:Blotting, Western; D002374:Catalase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008345:Manganese / Q000737:chemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008665:Metalloporphyrins / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D017382:Reactive Oxygen Species; D013481:Superoxides; D017665:Hydroxyl Radical; D008345:Manganese; D006861:Hydrogen Peroxide; D002374:Catalase; D005980:Glutathione Reductase; D005978:Glutathione; D001205:Ascorbic Acid