The biologic plausibility of an association between type 2 diabetes mellitus (T2D) and lung cancer has received increasing attention, but the results of investigations remain largely inconclusive. In the present study we investigated the influence of the anti-diabetic drug metformin on the cytotoxic effects of EGFR targeted therapy and chemotherapy in 7 non-small cell lung cancer (NSCLC) cell lines and a cohort of lung cancer patients with/without T2D. In vitro cell viability assays indicated that metformin didn't potentiate the growth inhibitory effects of erlotinib at different doses in cell lines that are of distinct genetic background. EGFR downstream signaling evaluation further demonstrated that metformin, at its IC50 value, modified apoptosis caused in erlotinib or chemotherapeutic agent-treated cells via AKT activation and the inhibition of caspase 3 and PARP cleavages. These regulations were driven independently from EGFR, LKB1, KRAS, PTEN and p53 status. Metformin triggered autophagy (LC3B expression) was identified to interplay with apoptosis to attenuate the drug effect and postpone cancer cell death. In the retrospective study of 8 NSCLC patients, the administration of metformin did not induce statistically significant changes as assessed by immunohistochemical staining of pERK, pAKT and cleaved PARP. Consequently, the application of metformin for T2D NSCLC patients receiving chemo or EGFR targeted therapy should be considered with caution.

中文翻译：

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二甲双胍触发自噬以减轻药物诱导的NSCLC细胞凋亡，对糖尿病患者的肿瘤影响较小。

2型糖尿病（T2D）与肺癌之间的生物学联系似乎越来越受到关注，但是研究结果仍然没有定论。在本研究中，我们研究了抗糖尿病药物二甲双胍对EGFR靶向治疗和化疗对7种非小细胞肺癌（NSCLC）细胞系和一组患有T2D /不患有T2D的肺癌患者的细胞毒性作用的影响。体外细胞生存力分析表明，二甲双胍在具有不同遗传背景的细胞系中以不同剂量并没有增强厄洛替尼的生长抑制作用。EGFR下游信号评估进一步证实了二甲双胍在其IC50值，经由AKT活化以及对caspase 3和PARP裂解的抑制作用而改变了在厄洛替尼或化学治疗剂处理的细胞中引起的细胞凋亡。这些法规独立于EGFR，LKB1，KRAS，PTEN和p53状态而驱动。已确定二甲双胍触发的自噬（LC3B表达）与细胞凋亡相互作用，以减弱药物作用和推迟癌细胞死亡。在对8例NSCLC患者的回顾性研究中，如通过pERK，pAKT和裂解的PARP的免疫组织化学染色所评估的那样，二甲双胍的给药未引起统计学上的显着变化。因此，应谨慎考虑将二甲双胍用于接受化学疗法或EGFR靶向治疗的T2D NSCLC患者。已确定二甲双胍触发的自噬（LC3B表达）与细胞凋亡相互作用，以减弱药物作用和推迟癌细胞死亡。在对8例NSCLC患者的回顾性研究中，如通过pERK，pAKT和裂解的PARP的免疫组织化学染色所评估的那样，二甲双胍的给药未引起统计学上的显着变化。因此，应谨慎考虑将二甲双胍用于接受化学疗法或EGFR靶向治疗的T2D NSCLC患者。已确定二甲双胍触发的自噬（LC3B表达）与细胞凋亡相互作用，以减弱药物作用和推迟癌细胞死亡。在对8例NSCLC患者的回顾性研究中，如通过pERK，pAKT和裂解的PARP的免疫组织化学染色所评估的那样，二甲双胍的给药未引起统计学上的显着变化。因此，应谨慎考虑将二甲双胍用于接受化学疗法或EGFR靶向治疗的T2D NSCLC患者。