title: Manganese porphyrin, MnTE-2-PyP5+, Acts as a pro-oxidant to potentiate glucocorticoid-induced apoptosis in lymphoma cells.
abstract: Using current chemotherapy protocols, over 55% of lymphoma patients fail treatment. Novel agents are needed to improve lymphoma survival. The manganese porphyrin, MnTE-2-PyP(5+), augments glucocorticoid-induced apoptosis in WEHI7.2 murine thymic lymphoma cells, suggesting that it may have potential as a lymphoma therapeutic. However, the mechanism by which MnTE-2-PyP(5+) potentiates glucocorticoid-induced apoptosis is unknown. Previously, we showed that glucocorticoid treatment increases the steady state levels of hydrogen peroxide ([H(2)O(2)](ss)) and oxidizes the redox environment in WEHI7.2 cells. In the current study, we found that when MnTE-2-PyP(5+) is combined with glucocorticoids, it augments dexamethasone-induced oxidative stress however, it does not augment the [H(2)O(2)](ss) levels. The combined treatment depletes GSH, oxidizes the 2GSH:GSSG ratio, and causes protein glutathionylation to a greater extent than glucocorticoid treatment alone. Removal of the glucocorticoid-generated H(2)O(2) or depletion of glutathione by BSO prevents MnTE-2-PyP(5+) from augmenting glucocorticoid-induced apoptosis. In combination with glucocorticoids, MnTE-2-PyP(5+) glutathionylates p65 NF-κB and inhibits NF-κB activity. Inhibition of NF-κB with SN50, an NF- κB inhibitor, enhances glucocorticoid-induced apoptosis to the same extent as MnTE-2-PyP(5+). Taken together, these findings indicate that: 1) H(2)O(2) is important for MnTE-2-PyP(5+) activity; 2) Mn-TE-2-PyP(5+) cycles with GSH; and 3) MnTE-2-PyP(5+) potentiates glucocorticoid-induced apoptosis by glutathionylating and inhibiting critical survival proteins, including NF-κB. In the clinic, over-expression of NF-κB is associated with a poor prognosis in lymphoma. MnTE-2-PyP(5+) may therefore, synergize with glucocorticoids to inhibit NF-κB and improve current treatment.
authors.affiliation: Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Melba C
authors.initials: MC
authors.lastname: Jaramillo
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Briehl
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Tome
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D013953:Thymus Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D005978:Glutathione