Metformin sensitizes AML cells to venetoclax through endoplasmic reticulum stress-CHOP pathway
Metformin sensitizes AML cells to venetoclax through endoplasmic reticulum stress-CHOP pathway
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DOI：
10.1111/bjh.18968
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发表时间：
2023-07-06
影响因子：
6.5
通讯作者：
Zeng，Hui
中科院分区：
文献类型：
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作者：
Hua，Lei;Yang，Nianhui;Zeng，Hui
维奈托克通过抑制BCL-2靶向作用抑制急性髓性白血病，已探索了与维奈托克的联合治疗方案。尽管这些方案产生了较好的临床效果，但绝大多数患者仍然遭受疾病复发或原发性耐药。已证明二甲双胍可诱导癌细胞凋亡。然而，它是否可以与维奈托克协同作用以及二甲双胍诱导细胞凋亡的潜在机制尚未完全了解。在本研究中，我们研究了二甲双胍和维奈托克对体外和体内AML细胞生长的影响。在Molm 13和THP-1细胞系中，二甲双胍和维奈托克协同抑制白血病细胞的增殖并诱导细胞凋亡。最重要的是，二甲双胍和维奈托克联合治疗显著增加了内质网（ER）应激相关标志物CHOP的表达水平，例如在AML细胞系中。CHOP的敲除显著减弱了二甲双胍和维奈托克诱导的细胞凋亡。此外，二甲双胍和维奈托克联合用药在异种移植模型和AML患者骨髓样本中显示出显著的抗白血病作用。总之，二甲双胍和维奈托克联合治疗在AML患者中显示出增强的抗白血病活性和可接受的安全性，代表了一种值得进一步临床研究的新的组合策略来治疗AML。
Venetoclax inhibits acute myeloid leukaemia by inhibiting BCL‐2 targeting, and a combination regimen with venetoclax has been explored. Although these regimens produce better clinical results, the vast majority of patients still suffer from disease recurrence or primary drug resistance. Metformin has been demonstrated to induce apoptosis in cancer cells. However, whether it can synergize with venetoclax and the underlying mechanisms of metformin‐induced apoptosis are not fully understood. In this study, we investigated the effect of metformin and venetoclax on the growth of AML cellsin vitroandin vivo. In both Molm13 and THP‐1 cell lines, metformin and venetoclax synergistically inhibited the proliferation and induced apoptosis of leukaemia cells. Most importantly, the combination of metformin and venetoclax treatment significantly increased the expression levels of the endoplasmic reticulum (ER) stress‐related marker CHOP, for example, in AML cell lines. Knockdown of CHOP markedly attenuated the metformin‐ and venetoclax‐induced cell apoptosis. Moreover, the combination of metformin and venetoclax demonstrated prominent anti‐leukaemia effects in xenograft models and bone marrow samples from AML patients. In summary, the combination of metformin and venetoclax showed enhanced anti‐leukaemia activity with acceptable safety in AML patients, representing a new combinatorial strategy worth further clinical investigation to treat AML.