title: Radioprotective effects of manganese-containing superoxide dismutase mimics on ataxia-telangiectasia cells.
abstract: We tested several classes of antioxidant manganese compounds for radioprotective effects using human lymphoblastoid cells: six porphyrins, three salens, and two cyclic polyamines. Radioprotection was evaluated by seven assays: XTT, annexin V and propidium iodide flow cytometry analysis, gamma-H2AX immunofluorescence, the neutral comet assay, dichlorofluorescein and dihydroethidium staining, resazurin, and colony survival assay. Two compounds were most effective in protecting wild-type and A-T cells against radiation-induced damage: MnMx-2-PyP-Calbio (a mixture of differently N-methylated MnT-2-PyP+ from Calbiochem) and MnTnHex-2-PyP. MnTnHex-2-PyP protected WT cells against radiation-induced apoptosis by 58% (p = 0.04), using XTT, and A-T cells by 39% (p = 0.01), using annexin V and propidium iodide staining. MnTnHex-2-PyP protected WT cells against DNA damage by 57% (p = 0.005), using gamma-H2AX immunofluorescence, and by 30% (p < 0.01), using neutral comet assay. MnTnHex-2-PyP is more lipophilic than MnMx-2-PyP-Calbio and is also >10-fold more SOD-active; consequently it is >50-fold more potent as a radioprotectant, as supported by six of the tests employed in this study. Thus, lipophilicity and antioxidant potency correlated with the magnitude of the beneficial radioprotectant effects observed. Our results identify a new class of porphyrinic radioprotectants for the general and radiosensitive populations and may also provide a new option for treating A-T patients.
authors.affiliation: Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Julianne M
authors.initials: JM
authors.lastname: Pollard
authors.forename: Julio S
authors.initials: JS
authors.lastname: Reboucas
authors.forename: Armando
authors.initials: A
authors.lastname: Durazo
authors.forename: Ivan
authors.initials: I
authors.lastname: Kos
authors.forename: Francesca
authors.initials: F
authors.lastname: Fike
authors.forename: Moeen
authors.initials: M
authors.lastname: Panni
authors.forename: Edith Butler
authors.initials: EB
authors.lastname: Gralla
authors.forename: Joan Selverstone
authors.initials: JS
authors.lastname: Valentine
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gatti
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D017209:Apoptosis; D001260:Ataxia Telangiectasia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism*; D002469:Cell Separation; D002478:Cells, Cultured; D020552:Comet Assay; D019610:Cytoprotection; D005434:Flow Cytometry; D006801:Humans; D008665:Metalloporphyrins / Q000737:chemistry / Q000378:metabolism; D011419:Propidium / Q000378:metabolism; D011837:Radiation-Protective Agents / Q000737:chemistry / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
chemical_list: D017304:Annexin A5; D000975:Antioxidants; D008665:Metalloporphyrins; C521294:Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin; D011837:Radiation-Protective Agents; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D011419:Propidium; D013482:Superoxide Dismutase