title: Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation.
abstract: Renewed interest in using pharmacological ascorbate (AscH-) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH- action in cancer cells is its ability to act as an electron donor to O2 for generating H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H2O2 fluxes and cytotoxicity. Three different MnPs were tested (MnTBAP, MnT2EPyP, and MnT4MPyP), exhibiting a range of physicochemical and thermodynamic properties. Of the MnPs tested, MnT4MPyP exerted the greatest effect on increasing the rate of AscH- oxidation as determined by the concentration of ascorbate radical [Asc•-] and the rate of oxygen consumption. At concentrations that had minimal effects alone, combining MnPs and AscH- synergized to decrease clonogenic survival in human pancreatic cancer cells. This cytotoxic effect was reversed by catalase, but not superoxide dismutase, consistent with a mechanism mediated by H2O2. MnPs increased steady-state concentrations of Asc•- upon ex vivo addition to whole blood obtained either from mice infused with AscH- or patients treated with pharmacologic AscH-. Finally, tumor growth in vivo was inhibited more effectively by combining MnT4MPyP with AscH-. We concluded that MnPs increase the rate of oxidation of AscH- to leverage H2O2 flux and ascorbate-induced cytotoxicity.
authors.affiliation: Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Malvika
authors.initials: M
authors.lastname: Rawal
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Schroeder
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.forename: Cameron M
authors.initials: CM
authors.lastname: Cushing
authors.forename: Jessemae L
authors.initials: JL
authors.lastname: Welsh
authors.forename: Anna M
authors.initials: AM
authors.lastname: Button
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Zita A
authors.initials: ZA
authors.lastname: Sibenaller
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Cullen
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008345:Manganese / Q000494:pharmacology; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D008665:Metalloporphyrins; D008345:Manganese; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D001205:Ascorbic Acid