Vorinostat and metformin sensitize EGFR-TKI resistant NSCLC cells via BIM-dependent apoptosis induction.
Vorinostat and metformin sensitize EGFR-TKI resistant NSCLC cells via BIM-dependent apoptosis induction.
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伏立诺他和二甲双胍通过 BIM 依赖性细胞凋亡诱导使 EGFR-TKI 耐药 NSCLC 细胞变得敏感。
DOI：
10.18632/oncotarget.21225
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发表时间：
2017-11-07
期刊：
影响因子：
--
通讯作者：
He Y
中科院分区：
文献类型：
--
作者：
Chen H;Wang Y;Lin C;Lu C;Han R;Jiao L;Li L;He Y
BIM的低表达与表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的耐药密切相关。Vorinostat是一种泛组蛋白去乙酰化酶抑制剂（HDACi），可增强BIM在各种类型肿瘤细胞中的表达，然而，在EGFR-TKI耐药的非小细胞肺癌（NSCLC）细胞中，抗凋亡蛋白的高表达减弱了这种作用。Vorinostat联合二甲双胍（一种可以抑制抗凋亡蛋白表达的化合物）可能协同激活凋亡信号并克服EGFR-TKI耐药性。本研究旨在探讨其协同效应并探讨可能的分子机制。结果显示，vorinostat联合吉非替尼增强了BIM表达，增加了EGFR-TKI耐药NSCLC细胞对吉非替尼的敏感性，同时加入二甲双胍可以明显抑制抗凋亡蛋白的表达，并进一步提高了BIM和BAX的表达水平，从而进一步提高了吉非替尼对EGFR-TKI固有耐药和获得性耐药的NSCLC细胞的敏感性。此外，二甲双胍可显著抑制吉非替尼和伏立诺他诱导的细胞自噬，这也可能有助于增强细胞凋亡，提高吉非替尼的敏感性。这些结果表明，vorinostat和二甲双胍联合使用可能是一种新的策略，可以在更大的异质人群中克服与bim依赖性凋亡相关的EGFR-TKI耐药性。
There is a close relationship between low expression of BIM and resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Vorinostat is a pan-histone deacetylase inhibitor (HDACi) that augments BIM expression in various types of tumor cells, however, this effect is attenuated by the high expression of anti-apoptotic proteins in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells. Vorinostat in combination with metformin – a compound that can inhibit anti-apoptotic proteins expression, might cooperate to activate apoptotic signaling and overcome EGFR-TKI resistance. This study aimed to investigate the cooperative effect and evaluate possible molecular mechanisms. The results showed that vorinostat combined with gefitinib augmented BIM expression and increased the sensitivity of EGFR-TKI resistant NSCLC cells to gefitinib, adding metformin simultaneously could obviously inhibit the expression of anti-apoptotic proteins, and further increased expression levels of BIM and BAX, and as a result, further improved the sensitivity of gefitinib both on the NSCLC cells with intrinsic and acquired resistance to EGFR-TKI. In addition, autophagy induced by gefitinib and vorinostat could be significantly suppressed by metformin, which might also contribute to enhance apoptosis and improve sensitivity of gefitinib. These results suggested that the combination of vorinostat and metformin might represent a novel strategy to overcome EGFR-TKI resistance associated with BIM-dependent apoptosis in larger heterogeneous populations.
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