Manganese porphyrin, MnTE-2-PyP 5+, acts as a pro-oxidant to potentiate glucocorticoid-induced apoptosis in lymphoma cells

Melba C. Jaramillo, Margaret M. Briehl, James D. Crapo, Ines Batinic-Haberle, Margaret E. Tome

Research output: Contribution to journalArticle

49 Scopus citations

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 2O 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 2O 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 2O 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 2O 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.

Original languageEnglish (US)
Pages (from-to)1272-1284
Number of pages13
JournalFree Radical Biology and Medicine
Volume52
Issue number8
DOIs
StatePublished - Apr 15 2012

Keywords

  • Dexamethasone
  • Glutathione
  • Glutathionylation
  • Hydrogen peroxide
  • Lymphoma
  • MnTE-2-PyP
  • NF-κB

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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