Radioprotective effects of manganese-containing superoxide dismutase mimics on ataxia-telangiectasia cells.
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.
Pollard
Julianne M
JM
Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Reboucas
Julio S
JS
Durazo
Armando
A
Kos
Ivan
I
Fike
Francesca
F
Panni
Moeen
M
Gralla
Edith Butler
EB
Valentine
Joan Selverstone
JS
Batinic-Haberle
Ines
I
Gatti
Richard A
RA
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*
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