RRC ID |
56051
|
著者 |
Ichii M, Oritani K, Murase M, Komatsu K, Yamazaki M, Kyoden R, Kito N, Nozaki Y, Saito M, Iwamura H, Kanakura Y.
|
タイトル |
Molecular targeting of inosine-5'-monophosphate dehydrogenase by FF-10501 promotes erythropoiesis via ROS/MAPK pathway.
|
ジャーナル |
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.
|
巻・号 |
59(2)
|
ページ |
448-459
|
公開日 |
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
|
引用数 |
2
|
リソース情報 |
ヒト・動物細胞 |
K562(RCB0027)
HL60
Jurkat
RPMI8226(RCB3010)
Raji |