| 包洋,李晓明,陈燕,等.组蛋白去乙酰化酶抑制剂联合 FMS样酪氨酸激酶 -3抑制剂对 FLT3-ITD突变白血病细胞增殖、凋亡和周期的影响[J].安徽医药,2023,27(5):894-900. |
| 组蛋白去乙酰化酶抑制剂联合 FMS样酪氨酸激酶 -3抑制剂对 FLT3-ITD突变白血病细胞增殖、凋亡和周期的影响 |
| Effects of HDACi combined with FLT3i on proliferation, apoptosis and cycle of FLT3-ITD (+) acute myelocytic leukemia cells |
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| DOI：10.3969/j.issn.1009-6469.2023.05.010 |
| 中文关键词: 白血病，髓样，急性 FMS样酪氨酸激酶 -3 组蛋白去乙酰化酶抑制剂 西达本胺 奎扎替尼 |
| 英文关键词: Leukemia,myeloid,acute FMS-like tyrosine kinase 3 Histone deacetylase inhibitor Chidamide Quizartinib |
| 基金项目:北京医学奖励基金会( YJHYXKYJJJ602)；四川省卫生健康委员会重点研究项目( 18zD014)；西南医科大学附属医院青年基金( 15045) |
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| 中文摘要: |
| 目的探讨组蛋白去乙酰化酶抑制剂( HDACi)联合 FMS样酪氨酸激酶 -3(FLT3)抑制剂对 FLT3-ITD突变的急性髓系白血病( AML)细胞系增殖抑制作用及其相关机制。方法将西达本胺( Chidamide)和奎扎替尼( Quizartinib，AC220)以不同浓度单药或联合作用于 MV4-11、MOLM-13细胞系 48 h后， CCK8检测细胞增殖能力； Compusyn 1.0软件分析两药联合作用的协同效应；流式细胞计数法测定各组细胞凋亡率、增殖周期；蛋白质印迹法测定 P53、Bcl-2、Bax、FLT3、磷酸化 FLT3(p-FLT3)及磷酸化 AKT(p-AKT)蛋白表达水平。结果随西达本胺及奎扎替尼单药或联合作用浓度升高，对 MV4-11及 MOLM-13细胞系的 48 h增殖抑制率均显著升高( P<0.05)并且两药具有协同抑制效应(均 CI值<1)。在奎扎替尼 1.0 nmol/L+西达本胺 1.0 μmol/L作用 48 h后，细胞凋亡率 MV4-11细胞株，为 31.697%±5.648%，MOLM-13细胞株为 18.500%±1.751%，细胞周期阻滞于 G0/G1期的比例 MV4-11细胞株为 78.493%±1.285%，MOLM-13细胞株为 89.850%±1.072%，两药联合较奎扎替尼 1.0 nmol/L或西达本胺 1.0 μmol/L单药使用可明显促进 MV4-11及 MOLM-13细胞系的凋亡和周期阻滞( P<0.05)。奎扎替尼 1.0 nmol/L联合西达本胺 1.0 μmol/L治疗较单药能更明显上调 P53、BAX促凋亡蛋白，下调 p-FLT3、抗凋亡蛋白 BCL-2及 PI3K/AKT信号通路关键下游因子 p-AKT。结论西达本胺与奎扎替尼联合应用可通过下调 p-FLT3、p-AKT、Bcl-2蛋白表达，上调 P53、Bax蛋白表达，促进 FLT3-ITD突变白血病细胞系的凋亡及周期阻滞，抑制 AML细胞的增殖活性。 |
| 英文摘要: |
| Objective This study was conducted to investigate whether histone deacetylase inhibitor (HDACi) combined with FMS-like tyrosine kinase 3 (FLT3) inhibitor can synergistically inhibit the proliferation of Acute myeloid leukemia (AML) cells with FLT3-In-ternal tandem duplication (ITD) and explore its related mechanisms, aiming to provide a preclinical basis for obtaining a more provendrug treatment modality for AML patients with FLT3-ITD mutation.Methods Chidamide and quizartinib were administered to MV4-11 and MOLM-13 cell lines at different concentrations alone or in combination for 48 h. The following assays were performed: CCK8 todetect cell proliferation ability.Compusyn 1.0 software was used to analyze the synergistic effect of the combination of the two drugs.Theapoptosis rate and proliferation cycle of each group were detected by flow cytomety.The expression levels of P53, Bcl-2, Bax, FLT3, p-FLT3 and p-AKT proteins, which are key downstream factors of PI3K/AKT signaling pathway were detected by Western-blotting.Re. sults Chidamide and quizartinib had proliferation inhibitory effects on MV4-11 and MOLM-13 cell lines in a dose-dependent manner. Chidamide combined with quizartinib had synergistic proliferation inhibitory effects on MV4-11 and MOLM-13 cell lines.Chidamide and quizartinib alone could promote the apoptosis and block the cell cycle of MV4-11 and MOLM-13 cell lines.Chidamide combined with quizartinib make more effects.The combination treatment with quizartinib and chidamide significantly up-regulated P53 and Bax pro-apoptotic protein, and down-regulated the expression of p-FLT3, anti-apoptotic protein Bcl-2 and p-Akt, a key downstream factor of PI3K/AKT signaling pathway, compared with single drug.Conclusion The combination of chidamide and quizartinib can promote theapoptosis and block the cell cycle of the AML cells,resulting in the suppression of the FLT3-ITD(+ ) AML cells, mainly through the downregulation of Bcl-2 and the upregulation of P53 and Bax proteins. |
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