1. Hematopoietic cell kinase (HCK) is a potential therapeutic target for dysplastic and leukemic cells due to integration of erythropoietin/PI3K pathway and regulation of erythropoiesis: HCK in erythropoietin/PI3K pathway.
- Author
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Roversi FM, Pericole FV, Machado-Neto JA, da Silva Santos Duarte A, Longhini AL, Corrocher FA, Palodetto B, Ferro KP, Rosa RG, Baratti MO, Verjovski-Almeida S, Traina F, Molinari A, Botta M, and Saad ST
- Subjects
- Adult, Aged, Cell Death drug effects, Erythropoiesis drug effects, Female, GATA1 Transcription Factor metabolism, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Male, Middle Aged, Molecular Targeted Therapy, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes metabolism, Young Adult, Enzyme Inhibitors pharmacology, Erythropoietin metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-hck antagonists & inhibitors, Proto-Oncogene Proteins c-hck metabolism, Signal Transduction drug effects
- Abstract
New drug development for neoplasm treatment is nowadays based on molecular targets that participate in the disease pathogenesis and tumor phenotype. Herein, we describe a new specific pharmacological hematopoietic cell kinase (HCK) inhibitor (iHCK-37) that was able to reduce PI3K/AKT and MAPK/ERK pathways activation after erythropoietin induction in cells with high HCK expression: iHCK-37 treatment increased leukemic cells death and, very importantly, did not affect normal hematopoietic stem cells. We also present evidence that HCK, one of Src kinase family (SFK) member, regulates early-stage erythroid cell differentiation by acting as an upstream target of a frequently deregulated pathway in hematologic neoplasms, PI3K/AKT and MAPK/ERK. Notably, HCK levels were highly increased in stem cells from patients with some diseases, as Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML), that are associated with ineffective erythropoiesis These discoveries support the exploration of the new pharmacological iHCK-37 in future preclinical and clinical studies., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2017
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