Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia

Less than a third of adults patients with acute myeloid leukemia (AML) are cured by current treatments, emphasizing the need for new approaches to therapy. We previously demonstrated that besides playing a role in drug-resistant leukemia cell lines, multidrug resistance protein 4 (MRP4/ABCC4) regulates leukemia cell proliferation and differentiation through the endogenous MRP4/ABCC4 substrate, cAMP. Here, we studied the role of MRP4/ABCC4 in tumor progression in a mouse xenograft model and in leukemic stem cells (LSCs) differentiation. We found a decrease in the mitotic index and an increase in the apoptotic index associated with the inhibition of tumor growth when mice were treated with rolipram (PDE4 inhibitor) and/or probenecid (MRPs inhibitor). Genetic silencing and pharmacologic inhibition of MRP4 reduced tumor growth. Furthermore, MRP4 knockdown induced cell cycle arrest and apoptosis in vivo. Interestingly, when LSC population was isolated, we observed that increased cAMP levels and MRP4/ABCC4 blockade resulted in LSCs differentiation. Taken together, our findings show that MRP4/ABCC4 has a relevant role in tumor growth and apoptosis and in the eradication of LSCs, providing the basis for a novel promising target in AML therapy.Fil: Copsel, Sabrina Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Bruzzone, Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: May, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Beyrath, Julien. Radboud Universiteit Nijmegen; Países BajosFil: Wargon, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Cany, Jeannette. Radboud Universiteit Nijmegen; Países BajosFil: Russel, Frans G. M.. Radboud Universiteit Nijmegen; Países BajosFil: Shayo, Carina Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Davio, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentin

SK channel-mediated metabolic escape to glycolysis inhibits ferroptosis and supports stress resistance in C. elegans

Metabolic flexibility is an essential characteristic of eukaryotic cells in order to adapt to physiological and environmental changes. Especially in mammalian cells, the metabolic switch from mitochondrial respiration to aerobic glycolysis provides flexibility to sustain cellular energy in pathophysiological conditions. For example, attenuation of mitochondrial respiration and/or metabolic shifts to glycolysis result in a metabolic rewiring that provide beneficial effects in neurodegenerative processes. Ferroptosis, a non-apoptotic form of cell death triggered by an impaired redox balance is gaining attention in the field of neurodegeneration. We showed recently that activation of small-conductance calcium-activated K+ (SK) channels modulated mitochondrial respiration and protected neuronal cells from oxidative death. Here, we investigated whether SK channel activation with CyPPA induces a glycolytic shift thereby increasing resilience of neuronal cells against ferroptosis, induced by erastin in vitro and in the nematode C. elegans exposed to mitochondrial poisons in vivo. High-resolution respirometry and extracellular flux analysis revealed that CyPPA, a positive modulator of SK channels, slightly reduced mitochondrial complex I activity, while increasing glycolysis and lactate production. Concomitantly, CyPPA rescued the neuronal cells from ferroptosis, while scavenging mitochondrial ROS and inhibiting glycolysis reduced its protection. Furthermore, SK channel activation increased survival of C. elegans challenged with mitochondrial toxins. Our findings shed light on metabolic mechanisms promoted through SK channel activation through mitohormesis, which enhances neuronal resilience against ferroptosis in vitro and promotes longevity in vivo

A Drosophila Mitochondrial Complex I Deficiency Phenotype Array

Mitochondrial diseases are a group of rare life-threatening diseases often caused by defects in the oxidative phosphorylation system. No effective treatment is available for these disorders. Therapeutic development is hampered by the high heterogeneity in genetic, biochemical, and clinical spectra of mitochondrial diseases and by limited preclinical resources to screen and identify effective treatment candidates. Alternative models of the pathology are essential to better understand mitochondrial diseases and to accelerate the development of new therapeutics. The fruit fly Drosophila melanogaster is a cost- and time-efficient model that can recapitulate a wide range of phenotypes observed in patients suffering from mitochondrial disorders. We targeted three important subunits of complex I of the mitochondrial oxidative phosphorylation system with the flexible UAS-Gal4 system and RNA interference (RNAi): NDUFS4 (ND-18), NDUFS7 (ND-20), and NDUFV1 (ND-51). Using two ubiquitous driver lines at two temperatures, we established a collection of phenotypes relevant to complex I deficiencies. Our data offer models and phenotypes with different levels of severity that can be used for future therapeutic screenings. These include qualitative phenotypes that are amenable to high-throughput drug screening and quantitative phenotypes that require more resources but are likely to have increased potential and sensitivity to show modulation by drug treatment

Design and synthesis of intrinsically cell-penetrating nucleopeptides.

International audienceNucleopeptides, which are constituted of alpha-amino acids bearing nucleobases at their side chains, are able to penetrate into cells and to reach the nucleus without cytotoxic effects

KH176 Safeguards Mitochondrial Diseased Cells from Redox Stress-Induced Cell Death by Interacting with the Thioredoxin System/Peroxiredoxin Enzyme Machinery

Contains fulltext : 191172.pdf (publisher's version ) (Open Access

Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity.

Item does not contain fulltextOngoing clinical trials are exploring anticancer approaches based on signaling by TRAIL, a ligand for the cell death receptors DR4 and DR5. In this study, we report on the selective apoptotic effects of multivalent DR5 binding peptides (TRAIL(mim/DR5)) on cancer cells in vitro and in vivo. Surface plasmon resonance revealed up to several thousand-fold increased affinities of TRAIL(mim/DR5)-receptor complexes on generation of divalent and trivalent molecules, the latter of which was achieved with a conformationally restricted adamantane core. Notably, only multivalent molecules triggered a substantial DR5-dependent apoptotic response in vitro. In tumor models derived from human embryonic kidney cells or primary foreskin fibroblasts, TRAIL(mim/DR5) peptides exerted a cancer cell-selective action that could synergize with resveratrol in a manner independent of p53. In a xenograft model of human colon cancer, a divalent TRAIL(mim/DR5) peptide inhibited tumor growth. Our results offer a proof-of-principle for the development of synthetic small molecules to trigger the TRAIL apoptosis pathway for cancer therapy

Additional file 4: Figure S2. of KH176 under development for rare mitochondrial disease: a first in man randomized controlled clinical trial in healthy male volunteers

Posthoc ECG assessment results. A. Change in QTcF (median increase from baseline; SAD study). B. Change in TpTe (median increase from baseline; SAD study). C. Change in the T-wave symmetry index (median increase from baseline; SAD study). D. Change in QTcF (median increase from baseline; SAD study). E. Change in TpTe (median increase from baseline; MAD study). F. Change in the T-wave symmetry index (median increase from baseline; MAD study). (PDF 341 kb