RRC ID 56051
Author Ichii M, Oritani K, Murase M, Komatsu K, Yamazaki M, Kyoden R, Kito N, Nozaki Y, Saito M, Iwamura H, Kanakura Y.
Title Molecular targeting of inosine-5'-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway.
Journal Leuk Lymphoma
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.
Volume 59(2)
Pages 448-459
Published 2018-2-1
DOI 10.1080/10428194.2017.1339878
PMID 28730859
MeSH Apoptosis / drug effects Bone Marrow Cells / cytology Bone Marrow Cells / drug effects Bone Marrow Cells / metabolism Case-Control Studies Cell Cycle / drug effects Cell Differentiation / drug effects Cell Line, Tumor Cell Lineage / drug effects Cell Proliferation / drug effects Enzyme Inhibitors / pharmacology* Erythropoiesis / drug effects* Hematopoietic Stem Cells / cytology Hematopoietic Stem Cells / drug effects Hematopoietic Stem Cells / metabolism Humans IMP Dehydrogenase / antagonists & inhibitors* MAP Kinase Signaling System / drug effects* Myelodysplastic Syndromes Phagocytosis / drug effects Phagocytosis / immunology Reactive Oxygen Species / metabolism*
IF 2.674
Times Cited 2
Human and Animal Cells K562(RCB0027) HL60 Jurkat RPMI8226(RCB3010) Raji