title: Differential effects of nitrostyrene derivatives on myelopoiesis involve regulation of C/EBPα and p38MAPK activity.
abstract: Bone marrow failure syndromes and MDS represent a heterogenous group of diseases, characterized by ineffective myelopoiesis, the risk of clonal evolution and a generally poor response to chemotherapy-based treatment regimen. Nitrostyrene derivatives have been studied as protein phosphatase inhibitors in various tumor models. Pharmacological studies have identified nitrostyrene as the structural core underlying a pro-apoptotic effect in tumor cells, yet their effects on normal cells, including those of the hematopoietic system, are largely unknown. In this study, utilizing umbilical cord blood-derived myeloid progenitor cells, patient-derived bone marrow cells, and a (BALB/c) mouse model; we investigated the effects of treatment with two nitrostyrene derivatives (NTS1 and NTS2) on myeloid development. We demonstrate that these compounds stimulate the expansion and differentiation of myeloid progenitors in vitro and improve myeloid reconstitution after chemotherapy-induced bone marrow depletion in vitro and in vivo. These effects were accompanied by increased C/EBPα expression and activity and inhibition of the p38MAPK signalling pathway. Together, our data suggest that nitrostyrenes improve myelopoiesis and represent potential new treatment strategies for patients suffering from bone marrow failure syndromes, hypocellular myelodysplastic syndrome and chemotherapy-induced aplasia.
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands; Division of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Bartels
authors.affiliation: Departamento de Farmacologica, Universidade Estadual de Campinas, Campinas/SP, Brazil.
authors.forename: Andrana K
authors.initials: AK
authors.lastname: Calgarotto
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Anton C
authors.initials: AC
authors.lastname: Martens
authors.affiliation: Departamento de Farmacologica, Universidade Estadual de Campinas, Campinas/SP, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Maso
authors.affiliation: Departamento de Química, Universidade Federal de São João Del-Rei, Ouro Branco/MG, Brazil.
authors.forename: Saulo L
authors.initials: SL
authors.lastname: da Silva
authors.affiliation: Division of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Bierings
authors.affiliation: Departamento de Farmacologica, Universidade Estadual de Campinas, Campinas/SP, Brazil.
authors.forename: Mary L
authors.initials: ML
authors.lastname: de Souza Queiroz
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands; Division of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D008807:Mice, Inbred BALB C; D038042:Myelopoiesis / Q000187:drug effects*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013343:Styrenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D013343:Styrenes; D048051:p38 Mitogen-Activated Protein Kinases