A Novel MnSOD Mimetic Targets Various Redox States to Selectively Treat Hematopoietic Malignancies via Control of AP-1 Signaling

Antioxidant compounds that can mimic the activity of endogenous enzymes via redox cycling offer a novel method of targeted cancer treatment. Here, we investigated the therapeutic effect of a mitochondrial- targeted, MnSOD mimetic, Mn(III) mesotetrakis (N-n-butoxyethylpyridinium-2yl) porphyrin, (MnTnBuOE) within sensitive and resistant myeloid lineage hematopoietic malignancies and utilize the hematopoietic disorder myelodysplastic syndrome (MDS) for the presentation of mechanistic insights to MnTnBuOE efficacy. MnTnBuOE treatment results in an increase in both CD34 + CD38 ‒ and CD34 + CD38 + normal stem/progenitor cell viability. Similar treatment shows significant cytotoxicity within AML and MDS models. Furthermore, manipulation of the cellular redox state via inhibition of glutathione synthesis, glutathione reductase activity, and treatment with glutathione disulfide sensitizes drug resistant CD34 + CML cells to MnTnBuOE treatment induced cytotoxicity. These results demonstrate glutathione metabolism and redox balance as a potential determinant of MnTnBuOE efficacy. Transcriptional analysis indicates that MnTnBuOE treatment initiates activator protein 1 (AP-1) activity in MDSL cells. DNA binding and immunoprecipitation identifies JunB as a transcriptional mediator of MnTnBuOE induced cytotoxicity. This is supported by siRNA knock down of JunB, resulting in protection against MnTnBuOE induced cytotoxicity. JunB precipitation via reaction with biotin-1,3-cyclopentadione demonstrates MnTnBuOE mediated oxidation of the JunB DNA binding region via hydrogen peroxide. This, in concert with co-immunoprecipitation of JunB, offers an alternative mechanism of JunB transcriptional activation through the identification of Ref-1; a protein specifically involved in the redox-modification of JunB. The finding that MnTnBuOE can target varying cellular redox states and exert selective cytotoxicity in malignant cells via differential activation of molecular pathways controlling lifespan and cell fate will significantly aid further development of safe, effective redox-active therapeutics for clinical applications.