Reference - Detail
| RRC ID | 68166 |
|---|---|
| Author | Katayama K, Nishihata A. |
| Title | RSK Inhibition Induces Apoptosis by Downregulating Protein Synthesis in a Variety of Acute Myeloid Leukemia Cell Lines. |
| Journal | Biol Pharm Bull |
| Abstract |
Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1/2 (IDH1/2) mutations drive malignancy in acute myeloid leukemia (AML), which accounts for approximately 40% of AML cases. Treatment with FLT3 or IDH1/2 inhibitors is used for such patients; however, it is not considered for most patients with AML who lack mutations on the respective genes. In this study, p90 ribosomal S6 kinase (RSK) was found to serve as a new therapeutic target in various AMLs with or without FLT3 mutations. BI-D1870, a potent inhibitor of RSK, significantly suppressed the proliferation of AML cell lines, among which three encoded wild-type FLT3 and three contained FLT3 driver mutations, compared with chronic myeloid leukemia K562 cells or other adherent cancer cells. BI-D1870 inhibited protein synthesis by dephosphorylating the p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in all AML cells except KG-1a cells. Meanwhile, the expression of microtubule-associated protein light chain 3B-I and -II increased in KG-1a cells treated with BI-D1870. BI-D1870 induced caspase-dependent apoptosis in all AML cells, including KG-1a cells. We next investigated the synergistic effect of BI-D1870 with cytarabine, a traditional anticancer drug used in AML. Synergistic effects of BI-D1870 and cytarabine were not observed in any of the cell lines. The findings suggested that BI-D1870 alone exerts an adequate antiproliferative effect on AML with or without FLT3 mutations and serves as a novel AML therapeutic agent. |
| Volume | 44(12) |
| Pages | 1843-1850 |
| Published | 2021-12-1 |
| DOI | 10.1248/bpb.b21-00531 |
| PMID | 34602526 |
| MeSH | Antineoplastic Agents / pharmacology* Antineoplastic Agents / therapeutic use Apoptosis Cell Line, Tumor Cell Proliferation Eukaryotic Initiation Factors / metabolism Humans Leukemia, Myeloid, Acute / drug therapy Leukemia, Myeloid, Acute / metabolism* Mutation Protein Biosynthesis / drug effects Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Pteridines / pharmacology* Pteridines / therapeutic use Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors* fms-Like Tyrosine Kinase 3 / genetics |
| IF | 1.863 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | KG-1a(RCB1928) |