TY - JOUR
T1 - Radioprotective effects of manganese-containing superoxide dismutase mimics on ataxia-telangiectasia cells
AU - Pollard, Julianne M.
AU - Reboucas, Julio S.
AU - Durazo, Armando
AU - Kos, Ivan
AU - Fike, Francesca
AU - Panni, Moeen
AU - Gralla, Edith Butler
AU - Valentine, Joan Selverstone
AU - Batinic-Haberle, Ines
AU - Gatti, Richard A.
N1 - Funding Information:
This work was supported by U.S. Public Health Grant NIH AI067769 (J.M.P. and R.A.G.) and Grant NIH DK46828 (J.S.V. and A.D.). I.B.H., I.K., and J.S.R. acknowledge support from NIAID Grant 5-U19-AI-067798-03 and the Wallace H. Coulter Translational Partners Grant Program. The authors also thank Dr. Rita Cantor for assistance with the statistical analyses for the ROS assays and Ms. Kelly Pettijohn for her assistance with the colony survival assay.
PY - 2009/8/1
Y1 - 2009/8/1
N2 - 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, γ-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 γ-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.
AB - 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, γ-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 γ-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.
KW - AEOL10112
KW - AEOL10113
KW - Ataxia-telangiectasia
KW - EUK-134
KW - EUK-189
KW - EUK-8
KW - Free radicals
KW - M40403
KW - M40404
KW - Mn cyclic polyamines
KW - Mn porphyrins
KW - Mn salens
KW - Radioprotection
KW - SOD mimics
UR - http://www.scopus.com/inward/record.url?scp=67349138879&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349138879&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2009.04.018
DO - 10.1016/j.freeradbiomed.2009.04.018
M3 - Article
C2 - 19389472
AN - SCOPUS:67349138879
SN - 0891-5849
VL - 47
SP - 250
EP - 260
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 3
ER -