IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response
文献类型：期刊论文
| 作者 | Yao, Mingyue6,7; Yan, Wenzhong5; Wang, Yafang6; Zhao, Yu4,6; Xu, Xiaowei3; Chen, Yujun4,6; Yu, Chengcheng7; Li, Yingnian7; Jiang, Hualiang2,4,6 ; Shen, Jie1
|
| 刊名 | EXPERIMENTAL HEMATOLOGY & ONCOLOGY
 |
| 出版日期 | 2025-02-15 |
| 卷号 | 14期号:1页码:19 |
| 关键词 | Acute myeloid leukemia HDAC inhibitor FLT3-ITD mutation DNA damage response Synergistic effect Drug resistance |
| DOI | 10.1186/s40164-025-00605-y |
| 通讯作者 | Shen, Jie(shj421@126.com) ; Cheng, Jianjun(chengjj@shanghaitech.edu.cn) ; Xie, Chengying(xiecy@lglab.ac.cn) |
| 英文摘要 | BackgroundDespite initial success with FLT3 inhibitors (FLT3is), outcomes for FLT3-ITD acute myeloid leukemia (AML) patients remain unsatisfactory, underscoring the need for more effective treatment options. Epigenetic modifications, such as histone acetylation, contribute to AML's onset and persistence, advocating the potential for epigenetic therapies. However, the poor specificity of pan-histone deacetylase inhibitors (HDACis) leads to undesirable adverse effects, prompting the need for isoform-specific HDACis. This study aims to explore the antileukemic activities and mechanisms of IHCH9033, a novel class I HDACi, alone or combined with FLT3i in FLT3-ITD AML.MethodsThe viability of AML cell lines and primary AML cells treated with HDACis alone or in combination with FLT3i was detected by MTT or CCK8 assay. Flow cytometry was utilized to examine cell apoptosis, cell cycle progression and ROS production. RNA sequencing analysis, RT-qPCR, western blotting, and co-immunoprecipitation assays were employed to elucidate the molecule mechanisms. The in vivo anti-leukemia efficacy was tested in xenografted mice models derived from FLT3-ITD cell lines and primary AML patients.ResultsHere, we identified IHCH9033, a novel selective class I HDACi, which exhibited an increased antitumor effect in FLT3-ITD AML through effectively eliminating leukemia burden and overcoming resistance to FLT3i. Mechanically, IHCH9033 selectively inhibited DNA repair in FLT3-ITD AML cells, leading to the accumulation of DNA damage that eventually resulted in cell cycle arrest and apoptosis. Additionally, IHCH9033 induced HSP90 acetylation, FLT3 ubiquitination, and proteasomal degradation of FLT3, thereby inhibiting FLT3 downstream signaling. Notably, IHCH9033 maintained its potency in both FLT3i-resistant AML cell lines and primary-resistant patient samples, and exerted strong synergy with the FLT3i quizartinib, leading to tumor regression in FLT3-ITD/TKD AML xenografts. In patient-derived xenografts, the treatment with IHCH9033, both alone and in combination, led to nearly complete eradication of the AML burden, without significant adverse effects.ConclusionsOur study shows that IHCH9033, a novel class I HDACi with a desirable pharmacological profile, is a promising drug candidate for FLT3-ITD AML, and suggests a strategy of combining class I HDACis and FLT3is in AML clinical trials to increase efficacy and overcome resistance, thus potentially providing a curative treatment option. |
| WOS关键词 | ACUTE MYELOID-LEUKEMIA ; HISTONE DEACETYLASE INHIBITOR ; INTERNAL TANDEM DUPLICATIONS ; DOUBLE-STRAND BREAKS ; GENOMIC INSTABILITY ; STEM-CELLS ; MUTATION ; REPAIR ; GENE ; HEAT-SHOCK-PROTEIN-90 |
| 资助项目 | Shanghai Super Postdoc Incentive Plan ; Molecular imaging platform of ShanghaiTech University ; Discovery technology platform of Shanghai Institute for Advanced Immunochemical Studies |
| WOS研究方向 | Oncology ; Hematology |
| 语种 | 英语 |
| WOS记录号 | WOS:001421647900002 |
| 出版者 | BMC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316239]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Shen, Jie; Cheng, Jianjun; Xie, Chengying |
| 作者单位 | 1.Shanghai Univ Tradit Chinese Med, Dept Pharm, SATCM Grade Lab Tradit Chinese Med Preparat 3, Shuguang Hosp, 528 Zhangheng Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai 201203, Peoples R China 3.Shanghai Jiao Tong Univ, Affiliated Shanghai Gen Hosp, Sch Med, Dept Hematol, Shanghai 200025, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.ShanghaiTech Univ, iHuman Inst, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China 6.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 7.Lingang Lab, 2380 Hechuan Rd, Shanghai 201101, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yao, Mingyue,Yan, Wenzhong,Wang, Yafang,et al. IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response[J]. EXPERIMENTAL HEMATOLOGY & ONCOLOGY,2025,14(1):19. |
| APA | Yao, Mingyue.,Yan, Wenzhong.,Wang, Yafang.,Zhao, Yu.,Xu, Xiaowei.,...&Xie, Chengying.(2025).IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response.EXPERIMENTAL HEMATOLOGY & ONCOLOGY,14(1),19. |
| MLA | Yao, Mingyue,et al."IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response".EXPERIMENTAL HEMATOLOGY & ONCOLOGY 14.1(2025):19. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。