Increased manganese superoxide dismutase expression or treatment with manganese porphyrin potentiates dexamethasone-induced apoptosis in lymphoma cells.
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 (H(2)O(2)) by catalase transfection or selection for H(2)O(2) resistance caused glucocorticoid resistance. This suggests the possibility that increasing H(2)O(2) sensitivity could sensitize the cells to glucocorticoids. In other cell types, increasing manganese superoxide dismutase (MnSOD) can increase intracellular H(2)O(2). The current study showed that increased expression of MnSOD sensitized WEHI7.2 cells to glucocorticoid-induced apoptosis and H(2)O(2). Treatment of WEHI7.2 cells with the catalytic antioxidant Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)), a manganoporphyrin, mimicked the effects of increased MnSOD expression. MnTE-2-PyP(5+) 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-PyP(5+) increased cell death due to dexamethasone. Treatment of H9c2 cardiomyocytes with MnTE-2-PyP(5+) inhibited doxorubicin cytotoxicity. The profile of MnTE-2-PyP(5+) effects suggests MnTE-2-PyP(5+) has potential for use in hematologic malignancies that are treated with glucocorticoids, cyclophosphamide, and doxorubicin.
Jaramillo
Melba C
MC
Department of Pathology, University of Arizona, Tucson, Arizona 85724, USA.
Frye
Jennifer B
JB
Crapo
James D
JD
Briehl
Margaret M
MM
Tome
Margaret E
ME
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008223:Lymphoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008224:Lymphoma, Follicular / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D011166:Porphyrins / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics*; D014162:Transfection
D005938:Glucocorticoids; D011166:Porphyrins; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase