Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species
Purpose: To examine the mechanism of radiation enhancement by motexafin gadolinium (Gd-Tex) in vitro. Methods and Materials: Oxidation of ascorbate and NADPH by Gd-Tex was evaluated in a neutral buffer. Growth inhibition of human uterine cancer cell line MES-SA was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Clonogenic assays were used to measure radiation response in MES-SA, A549 human lung carcinoma, E89, a CHO cell line variant deficient in glucose-6-phosphate dehydrogenase activity, and murine lymphoma cell lines LYAR and LYAS. Results: Gd-Tex catalyzed the oxidation of NADPH and ascorbate under aerobic conditions, forming hydrogen peroxide. Decreased viability was observed in MES-SA cells incubated with Gd-Tex in media containing NADPH or ascorbate. Gd-Tex and ascorbate increased fluorescence in dichlorofluorescin acetate-treated cultures. Synergistic effects on the aerobic radiation response in MES-SA and A549 were seen using Gd-Tex in combination with l-buthionine-(S,R)-sulfoximine (BSO). Incubation with Gd-Tex in the presence of ascorbate increased the aerobic radiation response of E89 and the apoptosis-sensitive B-cell line (LYAS). Conclusions: Gd-Tex sensitizes cells to ionizing radiation by increasing oxidative stress as a consequence of futile redox cycling. Optimization of the concentration of ascorbate (or other reducing species) may be required when evaluating Gd-Tex activity in vitro.
texaphyrin, radiation, sensitizer, ascorbate, superoxide
Magda, Darren, Cheryl Lepp, Nikolay Gerasimchuk, Intae Lee, Jonathan L. Sessler, Alice Lin, John E. Biaglow, and Richard A. Miller. "Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species." International Journal of Radiation Oncology Biology Physics 51, no. 4 (2001): 1025-1036.
International Journal of Radiation Oncology Biology Physics