在转化滤泡性淋巴瘤的临床前模型中,Venetoclax赋予奇达胺合成致死性。

IF 4.4 2区 医学 Q1 GENETICS & HEREDITY
Mengya Zhong, Guangchao Pan, Jinshui Tan, Jingwei Yao, Yating Liu, Jiewen Huang, Yuelong Jiang, Depeng Zhu, Jintao Zhao, Bing Xu, Jie Zha
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引用次数: 0

摘要

转化滤泡淋巴瘤(t-FL)是一种侵袭性和异质性的血液系统恶性肿瘤,治疗成功率有限;t-FL患者迫切需要开发新的治疗方法。在这里,我们使用t-FL细胞系和原代样品进行了高通量筛选(HTS)和体外实验,以评估组蛋白去乙酰化酶抑制剂chidamide和BCL-2抑制剂venetoclax的协同作用。在异种移植模型中进一步测试了体内疗效。在多个t-FL细胞系中,venetoclax和chidamide联合使用可显著抑制细胞增殖,诱导细胞凋亡,并将细胞周期阻滞在G0/G1期。此外,联合治疗有效地减轻了肿瘤负担,延长了异种移植模型的总生存期,并协同靶向患者样本,同时保留了正常的pbmc。从机制上说,这种组合破坏了线粒体膜电位并调节了Wnt信号通路,如Wnt3a、Wnt5a/b、β-catenin和磷酸化的GSK3β的蛋白表达水平降低。同时,联合方案通过抑制关键基因HDAC10和BCL-xL增强了各自的抗癌作用。综上所述,venetoclax联合齐达胺在t-FL的临床前模型中显示了一种有效的抗癌策略,值得进一步的临床试验来验证其治疗t-FL的有效性和安全性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Venetoclax confers synthetic lethality to chidamide in preclinical models with transformed follicular lymphoma.

Transformed follicular lymphoma (t-FL) is an aggressive and heterogeneous hematological malignancy with limited treatment success; the development of novel therapeutic approaches is urgently needed for patients with t-FL. Here, we conducted high-throughput screening (HTS) and in vitro experiments using t-FL cell lines and primary samples to assess the synergistic effects of the histone deacetylase inhibitor chidamide and the BCL-2 inhibitor venetoclax. In vivo efficacy was further tested in xenograft models. The combination of venetoclax and chidamide significantly inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in the G0/G1 phase across multiple t-FL cell lines. Furthermore, the combined therapy effectively reduced tumor burden, extended overall survival in xenograft models, and synergistically targeted patient samples, while sparing normal PBMCs. Mechanistically, this combination disrupted mitochondrial membrane potential and modulated the Wnt signaling pathway, as evidenced by decreased protein expression levels of Wnt3a, Wnt5a/b, β-catenin, and phosphorylated GSK3β. Concurrently, the combined regimen enhanced their respective anticancer effects by inhibiting the key genes HDAC10 and BCL-xL. Taken together, venetoclax combined with chidamide presents a potent anticancer strategy in preclinical models of t-FL and merits further exploration in clinical trials to validate its effectiveness and safety for treating t-FL.

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来源期刊
自引率
5.30%
发文量
150
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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