論文 - 詳細
| RRC ID | 62621 |
|---|---|
| 著者 | Nakatani K, Matsuo H, Harata Y, Higashitani M, Koyama A, Noura M, Nishinaka-Arai Y, Kamikubo Y, Adachi S. |
| タイトル | Inhibition of CDK4/6 and autophagy synergistically induces apoptosis in t(8;21) acute myeloid leukemia cells. |
| ジャーナル | Int J Hematol |
| Abstract |
The t(8;21) translocation is the most common cytogenetic abnormality in acute myeloid leukemia (AML). Although t(8;21) AML patients have a relatively favorable prognosis, relapse is a frequent occurrence, underscoring the need to develop novel therapeutic approaches. Here, we showed that t(8;21) AML is characterized by frequent mutation and overexpression of CCND2. Analysis of 19 AML cell lines showed that t(8;21) AML cells had lower IC50 values for the selective CDK4/6 inhibitors palbociclib and abemaciclib than non-t(8;21) AML cells. CDK4/6 inhibitors caused cell cycle arrest at G1 phase and impaired cell proliferation in t(8;21) AML cells. CDK4/6 inhibition decreased MAP-ERK and PI3K-AKT-mTOR signaling pathway activity, induced LC3B-I to LC3B-II conversion, and enhanced autophagosome formation, suggesting autophagy induction. Treatment of t(8;21) AML cells with the autophagy inhibitors chloroquine (CQ) or LY294002 in combination with the CDK4/6 inhibitor abemaciclib significantly increased the percentage of apoptotic (Annexin V positive) cells, whereas CQ or LY294002 single treatment had no significant effects. The effectiveness of co-inhibiting CDK4/6 and autophagy was confirmed in primary t(8;21) AML cells. The results suggest that the combination of CDK4/6 and autophagy inhibitors had a synergistic effect on inducing apoptosis, suggesting a novel therapeutic approach for the treatment of t(8;21) AML. |
| 巻・号 | 113(2) |
| ページ | 243-253 |
| 公開日 | 2021-2-1 |
| DOI | 10.1007/s12185-020-03015-4 |
| PII | 10.1007/s12185-020-03015-4 |
| PMID | 33068248 |
| MeSH | Apoptosis / genetics* Autophagy / genetics* Cell Line, Tumor Cell Proliferation / drug effects Chromosomes, Human, Pair 21 Chromosomes, Human, Pair 8 Cyclin D2 / genetics Cyclin-Dependent Kinase 4 / antagonists & inhibitors* Cyclin-Dependent Kinase 4 / genetics Cyclin-Dependent Kinase 6 / antagonists & inhibitors* Cyclin-Dependent Kinase 6 / genetics Gene Expression Gene Expression Regulation, Leukemic / drug effects Humans Leukemia, Myeloid, Acute / drug therapy Leukemia, Myeloid, Acute / genetics* Leukemia, Myeloid, Acute / metabolism Mutation Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use RNA Interference Signal Transduction / drug effects Translocation, Genetic* |
| IF | 2.245 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | pENTR4-H1tetOx1 (RDB07916) |
| ヒト・動物細胞 | THP-1(RCB1189) |