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12 results on '"Kinase activity"'

1. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

Author

Jacek Bielawski, Adrienne M. Dorrance, William Blum, Jason G. Harb, Rebecca B. Klisovic, Alistair Reid, Paolo Neviani, Stefano Volinia, Dragana Milojkovic, Carolyn Paisie, Mark Wunderlich, Ramasamy Santhanam, Denis-Claude Roy, Steffen Koschmieder, James C. Mulloy, Sahar A. Saddoughi, Ching-Shih Chen, Tessa L. Holyoake, Anna M. Eiring, Yihui Ma, Peter Hokland, Joshua J. Oaks, Jorge E. Cortes, Carlo M. Croce, Claudia S. Huettner, Steven M. Devine, Christopher J. Walker, Janelle A. Solt, Jane F. Apperley, Michael A. Caligiuri, Guido Marcucci, Hsiaoyin C. Mao, Justin Ellis, Ralph B. Arlinghaus, John M. Goldman, Bin Zhang, Ramiro Garzon, Ravi Bhatia, Chaode Sun, Gregory Ferenchak, Besim Ogretmen, Robert Bittman, Danilo Perrotti, John C. Byrd, and Philippa C. May

Subjects
Disease reservoir, Myeloid, Fusion Proteins, bcr-abl, Drug Resistance, Apoptosis, Mice, Sphingosine, hemic and lymphatic diseases, Protein Phosphatase 2, Wnt Signaling Pathway, beta Catenin, Leukemia, Myeloid leukemia, General Medicine, drug therapy, medicine.anatomical_structure, Neoplastic Stem Cells, Stem cell, Animals, Antineoplastic Agents, pharmacology, Apoptosis, Cell Proliferation, drug effects, Drug Resistance, Neoplasm, Enzyme Activators, pharmacology, Fusion Proteins, drug effects/enzymology, Humans, Janus Kinase 2, metabolism, K562 Cells, Leukemia, Myelogenous, BCR-ABL Positive, drug therapy, Mice, Neoplastic Stem Cells, drug effects/enzymology, Propylene Glycols, pharmacology, Protein Phosphatase 2, metabolism, Sphingosine, Tyrosine kinase, Research Article, Cell Survival, Enzyme Activators, Mice, Transgenic, Antineoplastic Agents, Biology, drug effects/enzymology, NO, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Animals, Humans, Kinase activity, Progenitor cell, Protein Kinase Inhibitors, Cell Proliferation, Fingolimod Hydrochloride, Fusion Proteins, Janus Kinase 2, Hematopoietic Stem Cells, medicine.disease, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm, Propylene Glycols, drug effects, Immunology, Neoplasm, pharmacology, K562 Cells, metabolism
Abstract

The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase–independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression — but not activity — of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/β-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase–independent and PP2A-mediated inhibition of JAK2 and β-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1–positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/β-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs.

Published
2013

2. Carbamoylating Activity Associated with the Activation of the Antitumor Agent Laromustine Inhibits Angiogenesis by Inducing ASK1-Dependent Endothelial Cell Death

Author

Yonghao Li, Huanjiao Jenny Zhou, Dylan J. Cincotta, Yun He, Wang Min, Roxanne Ghazvinian, Kevin P. Rice, Mei Yang, Weidong Ji, and Alexandra Praggastis

Subjects
Cell signaling, Angiogenesis, Cancer Treatment, lcsh:Medicine, Signal transduction, Methyl isocyanate, Vascular Medicine, chemistry.chemical_compound, Thioredoxins, Medicine and Health Sciences, ASK1, lcsh:Science, Cells, Cultured, Laromustine, Sulfonamides, Multidisciplinary, Protein Kinase Signaling Cascade, Cell Death, Pharmaceutics, Signaling Cascades, Endothelial stem cell, Hydrazines, Oncology, Biochemistry, Cancer Therapy, Antiangiogenesis Therapy, Thioredoxin, Research Article, Cell biology, Thioredoxin Reductase 1, Inflammatory Diseases, Immunoblotting, Neovascularization, Physiologic, Antineoplastic Agents, Biology, MAP Kinase Kinase Kinase 5, Drug Therapy, Chemotherapy, Animals, Humans, Mitogen-Activated Protein Kinase 8, Kinase activity, Molecular Biology, Pharmacology, Biology and life sciences, lcsh:R, Endothelial Cells, Protein kinase C signaling, In vitro, chemistry, Biocatalysis, Cattle, lcsh:Q, Carbamates, Isocyanates
Abstract

The anticancer agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine), upon decomposition in situ, yields methyl isocyanate and the chloroethylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE). 90CE has been shown to kill tumor cells via a proposed mechanism that involves interstrand DNA cross-linking. However, the role of methyl isocyanate in the antineoplastic function of laromustine has not been delineated. Herein, we show that 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE), an analog of laromustine that generates only methyl isocyanate, activates ASK1-JNK/p38 signaling in endothelial cells (EC). We have previously shown that ASK1 forms a complex with reduced thioredoxin (Trx1) in resting EC, and that the Cys residues in ASK1 and Trx1 are critical for their interaction. 101MDCE dissociated ASK1 from Trx1, but not from the phosphoserine-binding inhibitor 14-3-3, in whole cells and in cell lysates, consistent with the known ability of methyl isocyanate to carbamoylate free thiol groups of proteins. 101MDCE had no effect on the kinase activity of purified ASK1, JNK, or the catalytic activity of Trx1. However, 101MDCE, but not 90CE, significantly decreased the activity of Trx reductase-1 (TrxR1). We conclude that methyl isocyanate induces dissociation of ASK1 from Trx1 either directly by carbamoylating the critical Cys groups in the ASK1-Trx1 complex or indirectly by inhibiting TrxR1. Furthermore, 101MDCE (but not 90CE) induced EC death through a non-apoptotic (necroptotic) pathway leading to inhibition of angiogenesis in vitro. Our study has identified methyl isocyanates may contribute to the anticancer activity in part by interfering with tumor angiogenesis.

Published
2014

3. Necrostatin-1 Analogues: Critical Issues on the Specificity, Activity and In Vivo Use in Experimental Disease Models

Author

Sasker Grootjans, Peter Vandenabeele, George C. Prendergast, Junying Yuan, Anje Cauwels, Nozomi Takahashi, Alexei Degterev, Nico Callewaert, Wim Declercq, Vera Goossens, Linde Duprez, James B. DuHadaway, F. Van Hauwermeiren, Claude Libert, Wim Nerinckx, and Ria Roelandt

Subjects
Models, Molecular, Cancer Research, Indoles, RIPK1, Necroptosis, Immunology, necroptosis, Apoptosis, necrostatin, Pharmacology, Biology, IDO, sepsis, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, Drug Therapy, Species Specificity, In vivo, Cell Line, Tumor, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, SIRS, Kinase activity, Enzyme Inhibitors, Protein kinase A, 030304 developmental biology, 0303 health sciences, Molecular Structure, Imidazoles, Cell Biology, In vitro, digestive system diseases, Systemic Inflammatory Response Syndrome, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, 030220 oncology & carcinogenesis, Receptor-Interacting Protein Serine-Threonine Kinases, Toxicity, Tumor necrosis factor alpha, Female, Original Article
Abstract

Necrostatin-1 (Nec-1) is widely used in disease models to examine the contribution of receptor-interacting protein kinase (RIPK) 1 in cell death and inflammation. We studied three Nec-1 analogs: Nec-1, the active inhibitor of RIPK1, Nec-1 inactive (Nec-1i), its inactive variant, and Nec-1 stable (Nec-1s), its more stable variant. We report that Nec-1 is identical to methyl-thiohydantoin-tryptophan, an inhibitor of the potent immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). Both Nec-1 and Nec-1i inhibited human IDO, but Nec-1s did not, as predicted by molecular modeling. Therefore, Nec-1s is a more specific RIPK1 inhibitor lacking the IDO-targeting effect. Next, although Nec-1i was ∼100 × less effective than Nec-1 in inhibiting human RIPK1 kinase activity in vitro, it was only 10 times less potent than Nec-1 and Nec-1s in a mouse necroptosis assay and became even equipotent at high concentrations. Along the same line, in vivo, high doses of Nec-1, Nec-1i and Nec-1s prevented tumor necrosis factor (TNF)-induced mortality equally well, excluding the use of Nec-1i as an inactive control. Paradoxically, low doses of Nec-1 or Nec-1i, but not Nec -1s, even sensitized mice to TNF-induced mortality. Importantly, Nec-1s did not exhibit this low dose toxicity, stressing again the preferred use of Nec-1s in vivo. Our findings have important implications for the interpretation of Nec-1-based data in experimental disease models.

Published
2012
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4. Imatinib relaxes the pulmonary venous bed of guinea pigs.

Author

Maihöfer, Nina A., Suleiman, Said, Dreymüller, Daniela, Manley, Paul W., Rossaint, Rolf, Uhlig, Stefan, Martin, Christian, and Rieg, Annette D.

Subjects
PULMONARY hypertension treatment, DRUG therapy, IMATINIB, PLATELET-derived growth factor, TREATMENT effectiveness, PROTEIN-tyrosine kinases, THERAPEUTICS, PROTEIN metabolism, PULMONARY vein physiology, ANIMALS, VASODILATION, DOSE-effect relationship in pharmacology, GUINEA pigs, VASCULAR resistance, PULMONARY veins, VASODILATORS, PROTEIN kinase inhibitors
Abstract

Background: Recently, the IMPRES study revealed that systemic imatinib improves exercise capacity in patients with advanced pulmonary arterial hypertension. Imatinib blocks the tyrosine kinase activity of the platelet-derived growth factor (PDGF)-receptor (PDGFR), acts antiproliferative and relaxes pulmonary arteries. However so far, the relaxant effects of imatinib on pulmonary veins (PVs) and on the postcapillary resistance are unknown, although pulmonary hypertension (PH) due to left heart disease (LHD) is most common and primarily affects PVs. Next, it is unknown whether activation of PDGFR alters the pulmonary venous tone. Due to the reported adverse effects of systemic imatinib, we evaluated the effects of nebulized imatinib on the postcapillary resistance.Methods: Precision-cut lung slices (PCLS) were prepared from guinea pigs. PVs were pre-constricted with Endothelin-1 (ET-1) and the imatinib-induced relaxation was studied by videomicroscopy; PDGF-BB-related vascular properties were evaluated as well. The effects of perfused/nebulized imatinib on the postcapillary resistance were studied in cavine isolated perfused lungs (IPL). Intracellular cAMP/cGMP was measured by ELISA in PVs.Results: In PCLS, imatinib (100 μM) relaxed pre-constricted PVs (126%). In PVs, imatinib increased cAMP, but not cGMP and inhibition of adenyl cyclase or protein kinase A reduced the imatinib-induced relaxation. Further, inhibition of KATP-channels, [Formula: see text]-channels or Kv-channels diminished the imatinib-induced relaxation, whereas inhibition of NO-signaling was without effect. In the IPL, perfusion or nebulization of imatinib reduced the ET-1-induced increase of the postcapillary resistance. In PCLS, PDGF-BB contracted PVs, which was blocked by imatinib and by the PDGFR-β kinase inhibitor SU6668, whereas inhibition of PDGFR-α (ponatinib) had no significant effect. Conversely, PDGFR-β kinase inhibitors (SU6668/DMPQ) relaxed PVs pre-constricted with ET-1 comparable to imatinib, whereas the PDGFR-α kinase inhibitor ponatinib did not.Conclusions: Imatinib-induced relaxation depends on cAMP and on the activation of K+-channels. Perfused or nebulized imatinib significantly reduces the postcapillary resistance in the pre-constricted (ET-1) pulmonary venous bed. Hence, nebulization of imatinib is feasible and might reduce systemic side effects. Conversely, PDGF-BB contracts PVs by activation of PDGFR-β suggesting that imatinib-induced relaxation depends on PDGFR-β-antagonism. Imatinib combines short-term relaxant and long-term antiproliferative effects. Thus, imatinib might be a promising therapy for PH due to LHD. [ABSTRACT FROM AUTHOR]

Published
2017
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5. The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model.

Author

Matte, Alessandro, Federti, Enrica, Kung, Charles, Kosinski, Penelope, Narayanaswamy, Rohini, Russo, Roberta, Federico, Giorgia, Carlomagno, Francesca, Desbats, Maria, Salviati, Leonardo, Leboeuf, Christophe, Valenti, Maria, Turrini, Francesco, Janin, Anne, Yu, Shaoxia, Beneduce, Elisabetta, Ronseaux, Sebastien, Iatcenko, Iana, Dang, Lenny, Ganz, Tomas, Jung, Chun-Ling, Iolascon, Achille, Brugnara, Carlo, and De Franceschi, Lucia

Subjects
Drug therapy, Genetic diseases, Hematology, Mouse models, Animals, Disease Models, Animal, Enzyme Activators, Female, Hemolysis, Mice, Mice, Transgenic, Piperazines, Pyruvate Kinase, Quinolines, beta-Thalassemia
Abstract

Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbbth3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbbth3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in β-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing β-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with β-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for β-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.

Published
2021

6. Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy

Author

Elisabetta Cerbai, Corrado Poggesi, Iacopo Olivotto, Francesca Gentile, Alessandro Mugelli, Claudia Crocini, Raffaele Coppini, Leonardo Sacconi, Jil C. Tardiff, Josè Manuel Pioner, Matteo Rotellini, Gianluca Bartolucci, Annunziatina Laurino, Luca Mazzoni, Lorenzo Santini, V. Bargelli, Cecilia Ferrantini, Chiara Tesi, and Luiz Belardinelli

Subjects
Male, 0301 basic medicine, Inotrope, Time Factors, Cardiomyopathy, Ranolazine, cardiomyocyte, 030204 cardiovascular system & hematology, Ventricular Function, Left, Membrane Potentials, Ventricular Dysfunction, Left, 0302 clinical medicine, prevention, Heart Rate, Myocyte, Myocytes, Cardiac, sodium, Excitation Contraction Coupling, remodeling, Microscopy, Confocal, Hypertrophic cardiomyopathy, Magnetic Resonance Imaging, Echocardiography, Doppler, drug therapy, Phenotype, Hypertrophy, Left Ventricular, Cardiology and Cardiovascular Medicine, arrhythmias, Sodium Channel Blockers, medicine.drug, calcium, medicine.medical_specialty, Blotting, Western, Diastole, Mice, Transgenic, Article, 03 medical and health sciences, Troponin T, In vivo, Internal medicine, Ca2+/calmodulin-dependent protein kinase, medicine, Animals, Genetic Predisposition to Disease, business.industry, Cardiomyopathy, Hypertrophic, medicine.disease, Myocardial Contraction, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, Calcium-Calmodulin-Dependent Protein Kinases, Mutation, business
Abstract

Background— Current therapies are ineffective in preventing the development of cardiac phenotype in young carriers of mutations associated with hypertrophic cardiomyopathy (HCM). Ranolazine, a late Na + current blocker, reduced the electromechanical dysfunction of human HCM myocardium in vitro. Methods and Results— To test whether long-term treatment prevents cardiomyopathy in vivo, transgenic mice harboring the R92Q troponin-T mutation and wild-type littermates received an oral lifelong treatment with ranolazine and were compared with age-matched vehicle-treated animals. In 12-months-old male R92Q mice, ranolazine at therapeutic plasma concentrations prevented the development of HCM-related cardiac phenotype, including thickening of the interventricular septum, left ventricular volume reduction, left ventricular hypercontractility, diastolic dysfunction, left-atrial enlargement and left ventricular fibrosis, as evaluated in vivo using echocardiography and magnetic resonance. Left ventricular cardiomyocytes from vehicle-treated R92Q mice showed marked excitation–contraction coupling abnormalities, including increased diastolic [Ca 2+ ] and Ca 2+ waves, whereas cells from treated mutants were undistinguishable from those from wild-type mice. Intact trabeculae from vehicle-treated mutants displayed inotropic insufficiency, increased diastolic tension, and premature contractions; ranolazine treatment counteracted the development of myocardial mechanical abnormalities. In mutant myocytes, ranolazine inhibited the enhanced late Na + current and reduced intracellular [Na + ] and diastolic [Ca 2+ ], ultimately preventing the pathological increase of calmodulin kinase activity in treated mice. Conclusions— Owing to the sustained reduction of intracellular Ca 2+ and calmodulin kinase activity, ranolazine prevented the development of morphological and functional cardiac phenotype in mice carrying a clinically relevant HCM-related mutation. Pharmacological inhibitors of late Na + current are promising candidates for an early preventive therapy in young phenotype-negative subjects carrying high-risk HCM-related mutations.

Published
2017

7. Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in Echinococcus granulosus larval stage.

Author

Nicolao, María Celeste, Loos, Julia A., Rodriguez Rodrigues, Christian, Beas, Viviana, and Cumino, Andrea C.

Subjects
BORTEZOMIB, OXIDATIVE stress, AUTOPHAGY, ENDOPLASMIC reticulum, ECHINOCOCCOSIS, ECHINOCOCCUS granulosus, THERAPEUTICS
Abstract

Cystic echinococcosis (CE) is a worldwide distributed helminthic zoonosis caused by Echinococcus granulosus. Benzimidazole derivatives are currently the only drugs for chemotherapeutic treatment of CE. However, their low efficacy and the adverse effects encourage the search for new therapeutic targets. We evaluated the in vitro efficacy of Bortezomib (Bz), a proteasome inhibitor, in the larval stage of the parasite. After 96 h, Bz showed potent deleterious effects at a concentration of 5 μM and 0.5 μM in protoscoleces and metacestodes, respectively (P < 0.05). After 48 h of exposure to this drug, it was triggered a mRNA overexpression of chaperones (Eg-grp78 and Eg-calnexin) and of Eg-ire2/Eg-xbp1 (the conserved UPR pathway branch) in protoscoleces. No changes were detected in the transcriptional expression of chaperones in Bz-treated metacestodes, thus allowing ER stress to be evident and viability to highly decrease in comparison with protoscoleces. We also found that Bz treatment activated the autophagic process in both larval forms. These facts were evidenced by the increase in the amount of transcripts of the autophagy related genes (Eg-atg6, Eg-atg8, Eg-atg12, Eg-atg16) together with the increase in Eg-Atg8-II detected by western blot and by in toto immunofluorescence labeling. It was further confirmed by direct observation of autophagic structures by electronic microscopy. Finally, in order to determine the impact of autophagy induction on Echinococcus cell viability, we evaluated the efficacy of Bz in combination with rapamycin and a synergistic cytotoxic effect on protoscolex viability was observed when both drugs were used together. In conclusion, our findings demonstrated that Bz induced endoplasmic reticulum stress, autophagy and subsequent death allowing to identify unstudied parasite-host pathways that could provide a new insight for control of parasitic diseases. [ABSTRACT FROM AUTHOR]

Published
2017
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8. Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: preventive strategies and cardiovascular surveillance.

Author

Aghel, Nazanin, Delgado, Diego Hernan, and Lipton, Jeffrey Howard

Subjects
CARDIOTOXICITY, PROTEIN-tyrosine kinase inhibitors, ARTERIAL diseases, TREATMENT of chronic myeloid leukemia, CARDIOVASCULAR disease prevention, CARDIOVASCULAR disease diagnosis, PROTEIN metabolism, ANIMALS, ANTINEOPLASTIC agents, CARDIOVASCULAR diseases, DRUG therapy, DECISION making, PROTEINS, RISK assessment, MYELOID leukemia, PREDICTIVE tests, PATIENT selection, PROTEIN kinase inhibitors, CHEMICAL inhibitors
Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment and outcomes of chronic myeloid leukemia (CML). Despite their significant impact on the management of CML, there is growing evidence that TKIs may cause cardiovascular and/or metabolic complications. In this review, we present the current evidence regarding the cardiovascular safety profiles of BCR-ABL TKIs. Methodological challenges of studies that reported the cardiovascular safety of TKIs are discussed. We also propose management strategies for cardiovascular surveillance and risk factor modification during treatment with these agents. [ABSTRACT FROM AUTHOR]

Published
2017
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9. The Therapeutic Response of Gastrointestinal Stromal Tumors to Imatinib Treatment Assessed by Intravoxel Incoherent Motion Diffusion-Weighted Magnetic Resonance Imaging with Histopathological Correlation.

Author

Pan, Feng, Den, Jie, Zhang, Chunfang, Wang, He, Cheng, Jin, Wu, Weizhen, Hong, Nan, and Wang, Yi

Subjects
GASTROINTESTINAL tumors, GASTROINTESTINAL tumors treatment, IMATINIB, DRUG therapy, DIFFUSION magnetic resonance imaging, HISTOPATHOLOGY, DIAGNOSIS
Abstract

Purpose: To exploit the intravoxel incoherent motion (IVIM) diffusion-weighted (DW) MRI when evaluating the therapeutic response of gastrointestinal stromal tumors (GIST) to Imatinib in a mouse model. Materials and Methods: Mice with xenografts bearing cells from the GIST-T1 cell line were randomly divided into a treated group receiving Imatinib and a control group. DWMRI scans with 14 b-values (0–1500 s/mm2) were performed before and after treatment (days 1, 3 and 7). IVIM related parameters perfusion fractions (fp) and perfusion-related diffusion coefficients (D*) and the conventional apparent diffusion coefficients (ADC) were calculated by fitting the DWMRI signal decay. The mean changes from baseline to each post-treatment time point for each measurement (ΔADC, Δfp and ΔD*) were calculated. The differences of mean changes between the two groups were tested for statistical significance. Histopathological analyses including Ki-67, CD31, TUNEL and H&E were conducted in conjunction with the MRI scans. Results: Increases in ADC of the treated group were higher than those of the control group after treatment, whereas statistical significances were not observed. Compared to the control group, D* in the treated group decreased significantly (ΔD*treated = -41%, -49%, and -49% with P = 0.0001, 0.0001 and 0.0001), and fp increased significantly (Δfptreated = 79%, 82% and 110%, with P = 0.001, 0.0001 and P = 0.0007) on days 1, 3 and 7 after treatment. Histopathological analyses demonstrated different tumor tissue characteristics between the treated and control groups. Conclusion: IVIM measurements may serve as more sensitive imaging biomarkers than ADC when assessing GIST response to Imatinib as early as one day after treatment. [ABSTRACT FROM AUTHOR]

Published
2016
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10. A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration.

Author

Zhang, Liyun, Xiang, Lue, Liu, Yiwen, Venkatraman, Prahatha, Chong, Leelyn, Cho, Jin, Bonilla, Sylvia, Jin, Zi-Bing, Pang, Chi Pui, Ko, Kam Ming, Ma, Ping, Zhang, Mingzhi, and Leung, Yuk Fai

Subjects
RETINAL degeneration treatment, CHINESE medicine, DRUG development, IMMUNOSTAINING, GENETIC mutation, ANIMAL models in research
Abstract

Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime) carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf). The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR), a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants’ eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to extend functional vision in patients. [ABSTRACT FROM AUTHOR]

Published
2016
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11. Phosphatase inhibition by LB-100 enhances BMN-111 stimulation of bone growth

Author

Léa Loisay, Laurence Legeai-Mallet, Leia C. Shuhaibar, Laurinda A. Jaffe, Giulia Vigone, Thibault Horville, Jeremy R. Egbert, Tracy F. Uliasz, Emilie Dambroise, Martin Biosse Duplan, Nabil Kaci, Richard E. Honkanen, and Mark R. Swingle

Subjects
0301 basic medicine, Agonist, medicine.medical_specialty, medicine.drug_class, Primary Cell Culture, Therapeutics, Piperazines, Chondrocyte, Achondroplasia, Dephosphorylation, Mice, 03 medical and health sciences, Bone biology, Chondrocytes, 0302 clinical medicine, Bone disease, Internal medicine, medicine, Animals, Receptor, Fibroblast Growth Factor, Type 3, Growth Plate, Enzyme Inhibitors, Phosphorylation, Vosoritide, Bone growth, Bone Diseases, Developmental, Bone Development, Tibia, Chemistry, Cell Differentiation, Drug Synergism, Natriuretic Peptide, C-Type, Organ Size, General Medicine, Fibroblast growth factor receptor 3, NPR2, Phosphoric Monoester Hydrolases, Cartilage, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Medicine, Drug therapy, Receptors, Atrial Natriuretic Factor, Research Article
Abstract

Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations in the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase both result in decreased production of cyclic GMP in chondrocytes and severe short stature, causing achondroplasia (ACH) and acromesomelic dysplasia, type Maroteaux, respectively. Previously, we showed that an NPR2 agonist BMN-111 (vosoritide) increases bone growth in mice mimicking ACH (Fgfr3Y367C/+). Here, because FGFR3 signaling decreases NPR2 activity by dephosphorylating the NPR2 protein, we tested whether a phosphatase inhibitor (LB-100) could enhance BMN-111-stimulated bone growth in ACH. Measurements of cGMP production in chondrocytes of living tibias, and of NPR2 phosphorylation in primary chondrocytes, showed that LB-100 counteracted FGF-induced dephosphorylation and inactivation of NPR2. In ex vivo experiments with Fgfr3Y367C/+ mice, the combination of BMN-111 and LB-100 increased bone length and cartilage area, restored chondrocyte terminal differentiation, and increased the proliferative growth plate area, more than BMN-111 alone. The combination treatment also reduced the abnormal elevation of MAP kinase activity in the growth plate of Fgfr3Y367C/+ mice and improved the skull base anomalies. Our results provide a proof of concept that a phosphatase inhibitor could be used together with an NPR2 agonist to enhance cGMP production as a therapy for ACH.

Published
2021

12. The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model

Author

Charles Kung, Carlo Brugnara, Maria Teresa Valenti, Sebastien Ronseaux, Iana Iatcenko, Tomas Ganz, Anne Janin, Penelope A. Kosinski, Rohini Narayanaswamy, Leonardo Salviati, Achille Iolascon, Francesca Carlomagno, Shaoxia Yu, Giorgia Federico, Enrica Federti, Lucia De Franceschi, Chun-Ling Jung, Alessandro Matte, Roberta Russo, Francesco Michelangelo Turrini, Elisabetta Beneduce, Christophe Leboeuf, Maria Andrea Desbats, Lenny Dang, Università degli studi di Verona = University of Verona (UNIVR), Agios Pharmaceuticals, CEINGE - Biotecnologie Avanzate, University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi di Padova = University of Padua (Unipd), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli studi di Torino = University of Turin (UNITO), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), University of California [Los Angeles] (UCLA), University of California (UC), Harvard Medical School [Boston] (HMS), leboeuf, Christophe, Matte, A., Federti, E., Kung, C., Kosinski, P. A., Narayanaswamy, R., Russo, R., Federico, G., Carlomagno, F., Desbats, M. A., Salviati, L., Leboeuf, C., Valenti, M. T., Turrini, F., Janin, A., Yu, S., Beneduce, E., Ronseaux, S., Iatcenko, I., Dang, L., Ganz, T., Jung, C. -L., Iolascon, A., Brugnara, C., and De Franceschi, L.

Subjects
0301 basic medicine, Ineffective erythropoiesis, thalassemia, Enzyme Activator, Genetic disease, Quinoline, medicine.disease_cause, Mouse models, Transgenic, Piperazines, Mice, 0302 clinical medicine, hemic and lymphatic diseases, Glycolysis, Chemistry, General Medicine, Hematology, Erythroferrone, Hemolysis, 030220 oncology & carcinogenesis, Drug therapy, Genetic diseases, Animals, Disease Models, Animal, Enzyme Activators, Female, Mice, Transgenic, Pyruvate Kinase, Quinolines, beta-Thalassemia, Erythropoiesis, HAMP, medicine.drug, Research Article, medicine.medical_specialty, Hemolysi, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Mouse model, 03 medical and health sciences, Internal medicine, medicine, Piperazine, ineffective erythropoiesis, [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], Animal, medicine.disease, 030104 developmental biology, Endocrinology, Erythropoietin, Disease Models, iron homeostasis, Pyruvate kinase
Abstract

International audience; Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbb th3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbb th3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in β-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing β-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with β-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for β-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.

Published
2021

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