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Increased Manganese Superoxide Dismutase Expression or Treatment with Manganese Porphyrin Potentiates Dexamethasone-Induced Apoptosis in Lymphoma Cells

¹ Department of Pathology, University of Arizona, Tucson, Arizona and ² Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado

Requests for reprints: Margaret E. Tome, Department of Pathology, P.O. Box 245043, University of Arizona, Tucson, AZ 85724. Phone: 520-626-6771; Fax: 520-626-1027; E-mail: mtome{at}email.arizona.edu.

Key Words: SOD2 • AEOL 10113

Glucocorticoid-induced apoptosis is exploited for the treatment of hematologic malignancies. Innate and acquired resistance limits treatment efficacy; however, resistance mechanisms are not well understood. Previously, using WEHI7.2 murine thymic lymphoma cells, we found that increasing the resistance to hydrogen peroxide (H₂O₂) by catalase transfection or selection for H₂O₂ resistance caused glucocorticoid resistance. This suggests the possibility that increasing H₂O₂ sensitivity could sensitize the cells to glucocorticoids. In other cell types, increasing manganese superoxide dismutase (MnSOD) can increase intracellular H₂O₂. The current study showed that increased expression of MnSOD sensitized WEHI7.2 cells to glucocorticoid-induced apoptosis and H₂O₂. Treatment of WEHI7.2 cells with the catalytic antioxidant Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP⁵⁺), a manganoporphyrin, mimicked the effects of increased MnSOD expression. MnTE-2-PyP⁵⁺ also sensitized WEHI7.2 cells to cyclophosphamide and inhibited cell growth; it had no effect on the WEHI7.2 cell response to doxorubicin or vincristine. In primary follicular lymphoma cells, MnTE-2-PyP⁵⁺ increased cell death due to dexamethasone. Treatment of H9c2 cardiomyocytes with MnTE-2-PyP⁵⁺ inhibited doxorubicin cytotoxicity. The profile of MnTE-2-PyP⁵⁺ effects suggests MnTE-2-PyP⁵⁺ has potential for use in hematologic malignancies that are treated with glucocorticoids, cyclophosphamide, and doxorubicin. [Cancer Res 2009;69(13):5450–7]