Thioredoxin reductase is a major regulator of metabolism in leukemia cells.

Despite the fact that AML is the most common acute leukemia in adults, patient outcomes are poor necessitating the development of novel therapies. We identified that inhibition of Thioredoxin Reductase (TrxR) is a promising strategy for AML and report a highly potent and specific inhibitor of TrxR, S-250. Both pharmacologic and genetic inhibition of TrxR impairs the growth of human AML in mouse models. We found that TrxR inhibition leads to a rapid and marked impairment of metabolism in leukemic cells subsequently leading to cell death. TrxR was found to be a major and direct regulator of metabolism in AML cells through impacts on both glycolysis and the TCA cycle. Studies revealed that TrxR directly regulates GAPDH leading to a disruption of glycolysis and an increase in flux through the pentose phosphate pathway (PPP). The combined inhibition of TrxR and the PPP led to enhanced leukemia growth inhibition. Overall, TrxR abrogation, particularly with S-250, was identified as a promising strategy to disrupt AML metabolism.

Affinity of plant viral nanoparticle potato virus X (PVX) towards malignant B cells enables cancer drug delivery.

Non-Hodgkin's B cell lymphomas (NHL) include a diverse set of neoplasms that constitute ∼90% of all lymphomas and the largest subset of blood cancers. While chemotherapy is the first line of treatment, the efficacy of contemporary chemotherapies is hampered by dose-limiting toxicities. Partly due to suboptimal dosing, ∼40% of patients exhibit relapsed or refractory disease. Therefore more efficacious drug delivery systems are urgently needed to improve survival of NHL patients. In this study we demonstrate a new drug delivery platform for NHL based on the plant virus Potato virus X (PVX). We observed a binding affinity of PVX towards malignant B cells. In a metastatic mouse model of NHL, we show that systemically administered PVX home to tissues harboring malignant B cells. When loaded with the chemotherapy monomethyl auristatin (MMAE), the PVX nanocarrier enables effective delivery of MMAE to human B lymphoma cells in a NHL mouse model leading to inhibition of lymphoma growth in vivo and improved survival. Thus, PVX nanoparticle is a promising drug delivery platform for B cell malignancies.

Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington's disease.

Mitochondrial dysfunction is a major cytopathology in Huntington's disease (HD), a fatal and inherited neurodegenerative disease. However, the molecular mechanisms by which the disease-causing gene, mutant Huntingtin (mtHtt), affects mitochondrial function remains elusive. This study aims to determine the role that Mitogen-activated protein kinase 1 (MAPK1) plays in the over-activation of Dynamin-related protein 1 (Drp1), the mitochondrial fission protein, which leads to mitochondrial dysfunction and neurodegeneration seen in HD. We show that MAPK1 binds to and phosphorylates Drp1 in vitro. Drp1 phosphorylation at serine 616 is increased in HD knock-in mouse derived striatal cells, which is abolished by treatment with U0126, a potent inhibitor of MEK1/2. A phosphorylation-deficient mutant of Drp1, Drp1S616A, corrects mitochondrial fragmentation associated with HD. Treatment with U0126 also reduces mitochondrial fragmentation, but has no additional effect in correcting aberrant mitochondrial morphology in cells expressing Drp1S616A. Finally, treatment with U0126 reduces mitochondrial depolarization and mitochondrial superoxide production in HD mutant striatal cells when compared to wildtype cells. This study suggests that in HD, MAPK1 activation leads to the aberrant mitochondrial fission and mitochondrial function by phosphorylating Drp1. Therefore, inhibition of Drp1-mediated excessive mitochondrial fission might be a strategy for development of therapy for treating HD.