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: Melba C Jaramillo, Margaret M Briehl, James D Crapo, Ines Batinic-Haberle, Margaret E Tome
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 52 Issue 8 Pg. 1272-84 (Apr 15 2012) ISSN: 1873-4596 [Electronic] United States
• PMID: 22330065 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Metalloporphyrins
• Reactive Oxygen Species
• manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin
• Dexamethasone
• Hydrogen Peroxide
• Glutathione

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Dexamethasone (pharmacology)
• Drug Synergism
• Glutathione (metabolism)
• Hydrogen Peroxide (metabolism)
• Lymphoma (metabolism, pathology)
• Metalloporphyrins (pharmacology)
• Mice
• Oxidation-Reduction
• Reactive Oxygen Species (metabolism, pharmacology)
• Thymus Neoplasms (metabolism, pathology)