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Molecular targeting of inosine-5’-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway
- Source :
- Leukemia & Lymphoma. 59:448-459
- Publication Year :
- 2017
- Publisher :
- Informa UK Limited, 2017.
-
Abstract
- One of the major symptoms of myelodysplastic syndromes (MDS) is severe cytopenia. Despite cytokine therapies, such as erythropoiesis-stimulating agents, many patients still require blood transfusions, and the development of new therapeutic approaches is needed. In this work, we studied the effects of the inosine-5'-monophosphate (IMP) dehydrogenase (IMPDH) inhibitor FF-10501 on erythropoiesis of human hematopoietic cells. Differentiation of K562 chronic myeloid leukemia cells to an erythroid lineage was promoted by FF-10501 in a dose-dependent manner. Interestingly, we found that metabolic conversion of IMP to hypoxanthine leads to elevation of reactive oxygen species (ROS). The differentiative effects of FF-10501 were abolished by the ROS scavenger dimethylthiourea or the p38 MAPK inhibitor SB203580. Furthermore, FF-10501 promoted erythropoiesis from CD34+ hematopoietic stem/progenitor cells, accompanied with ROS accumulation, while high-dose FF-10501 mainly showed cytotoxic effects. These findings denote the potential of IMPDH inhibition therapy with FF-10501 in amelioration of anemia in MDS patients.
- Subjects :
- 0301 basic medicine
Cancer Research
MAP Kinase Signaling System
medicine.medical_treatment
Apoptosis
Bone Marrow Cells
03 medical and health sciences
IMP Dehydrogenase
0302 clinical medicine
Phagocytosis
Cell Line, Tumor
hemic and lymphatic diseases
medicine
Humans
Cell Lineage
Erythropoiesis
Enzyme Inhibitors
Inosine-5′-monophosphate dehydrogenase
Progenitor cell
Cell Proliferation
biology
Myelodysplastic syndromes
Cell Cycle
Myeloid leukemia
Cell Differentiation
Hematology
Hematopoietic Stem Cells
medicine.disease
Haematopoiesis
030104 developmental biology
Cytokine
Oncology
Case-Control Studies
Myelodysplastic Syndromes
030220 oncology & carcinogenesis
Immunology
biology.protein
Cancer research
Reactive Oxygen Species
K562 cells
Subjects
Details
- ISSN :
- 10292403 and 10428194
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Leukemia & Lymphoma
- Accession number :
- edsair.doi.dedup.....6645fdba8554393edced20ed057f7a4e