279 - Manganese Porphyrin, MnTE-2-PyP5+, Enhances Chemotherapeutic Response in Hematological Malignancies

Abstract

The prognosis for multiple myeloma (MM) and the activated B-cell subtype of diffuse large B-cell lymphoma (ABC DLBCL) are poor. Gene expression profiling studies have revealed that nuclear factor kappa-B (NF-kB), a critical survival protein, is constitutively active in MM and ABC DLBCL, and contributes to the poor prognosis. Use of agents that target NF-kB have the potential to improve patient outcome. Our laboratory, previously demonstrated that Mn(III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP5+), a redox cycling agent, acts as a pro-oxidant to enhance glucocorticoid-induced apoptosis in WEHI7.2 murine lymphoma cells. An increase in H2O2 and the presence of GSH are critical for the porphyrin’s ability to cause this effect. Alone, MnTE-2-PyP5+ was neither able to increase oxidative stress nor induce apoptosis. In the presence of dexamethasone, a synthetic glucocorticoid, MnTE-2-PyP5+ redox cycles with GSH, glutathionylates the p65 NF-kB subunit, and inhibits NF-kB activity in WEHI7.2 cells. Collectively these studies suggest that MnTE-2-PyP5+ is likely to enhance apoptosis in oxidized environments or in combination with other agents that increase H2O2 levels and in cells that overexpress NF-kB. In this study we found that MnTE-2-PyP5+ synergized with the drugs that are standard of care for DLBCL (cyclophosphamide, doxorubicin, vincristine and glucocorticoids) to enhance cell death in DLBCL human cell lines. The ABC DLBCL cells were also sensitive to MnTE-2-PyP5+ alone. In addition, DLBCL cells with increased C-MYC and BCL-2, which models a DLBCL patient population that also has a poor prognosis, were sensitive to MnTE-2-PyP5+ alone. In MM cells, MnTE-2-PyP5+ synergized with glucocorticoids and bortezomib to enhance cell death. Both drugs increase H2O2 and are used for the treatment of MM. These findings suggest that the addition of MnTE-2-PyP5+ to the standard therapy for DLBCL and MM may overcome NF-kB-mediated survival, enhance cell death, and ultimately improve patient survival.