title: Cytotoxic effects of Mn(III) N-alkylpyridylporphyrins in the presence of cellular reductant, ascorbate.
abstract: Due to the ability to easily accept and donate electrons Mn(III)N-alkylpyridylporphyrins (MnPs) can dismute O(2)(·-), reduce peroxynitrite, but also generate reactive species and behave as pro-oxidants if conditions favour such action. Herein two ortho isomers, MnTE-2-PyP(5+), MnTnHex-2-PyP(5+), and a meta isomer MnTnHex-3-PyP(5+), which differ greatly with regard to their metal-centered reduction potential, E(1/2) (Mn(III)P/Mn(II)P) and lipophilicity, were explored. Employing Mn(III)P/Mn(II)P redox system for coupling with ascorbate, these MnPs catalyze ascorbate oxidation and thus peroxide production. Consequently, cancer oxidative burden may be enhanced, which in turn would suppress its growth. Cytotoxic effects on Caco-2, Hela, 4T1, HCT116 and SUM149 were studied. When combined with ascorbate, MnPs killed cancer cells via peroxide produced outside of the cell. MnTE-2-PyP(5+) was the most efficacious catalyst for peroxide production, while MnTnHex-3-PyP(5+) is most prone to oxidative degradation with H(2) , and thus the least efficacious. A 4T1 breast cancer mouse study of limited scope and success was conducted. The tumour oxidative stress was enhanced and its microvessel density reduced when mice were treated either with ascorbate or MnP/ascorbate; the trend towards tumour growth suppression was detected.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ye
authors.forename: Diane
authors.initials: D
authors.lastname: Fels
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Aird
authors.forename: Casey
authors.initials: C
authors.lastname: Dedeugd
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Allensworth
authors.forename: Ivan
authors.initials: I
authors.lastname: Kos
authors.forename: Won
authors.initials: W
authors.lastname: Park
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Kam W
authors.initials: KW
authors.lastname: Leong
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells; D002384:Catalysis; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007536:Isomerism; D008665:Metalloporphyrins / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010545:Peroxides / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D019163:Reducing Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D008665:Metalloporphyrins; C521294:Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin; D010545:Peroxides; D017382:Reactive Oxygen Species; D019163:Reducing Agents; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin; D001205:Ascorbic Acid