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 language||English (US)|
|Number of pages||13|
|Journal||Free Radical Biology and Medicine|
|State||Published - Apr 15 2012|
- Hydrogen peroxide
ASJC Scopus subject areas
- Physiology (medical)