Xiao Di, Peng Mei, Deng Yang, Xiao Yayi, Chen Xinyi, Ma Lan, Tang Bei, Guo Chenglin, Yang Xiaoping
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Department of Pharmacy, School of Medicine, Hunan Normal University Changsha 410013, Hunan, China.
Am J Transl Res. 2021 Sep 15;13(9):10193-10205. eCollection 2021.
Lung cancer is among the diseases with the highest rates of morbidity and mortality. Our previous study found that a novel biguanide derivative, 1-n-heptyl-5-(3, 4-difluorophenyl) biguanide (8e) shows excellent anti-proliferative activity in non-small cell lung cancer (NSCLC) cell line A549. However, the underlying mechanism remains elusive. In this research, we analyzed the effect of 8e on NSCLC cell lines and explored the cell death mechanism caused by 8e. From our data, we found that 8e significantly decreased the cell activity and inhibited the colony formation of A549 and H1299 cells in a dose-dependent manner. Interestingly, this inhibitory effect of 8e was significantly reduced after silencing EGFR with lentiviral vectors. In contrast, after overexpressing EGFR in A549 and H1299, the lethality of 8e to the tumor cells increased. Simultaneously, we observed that 8e inhibited the expression of EGFR and its two essential downstream signaling pathways, AKT/mTOR and c-Raf/ERK1/2, and significantly reduced the activation of the EGFR pathway induced by EGF. Therefore, the results showed that 8e inhibits the proliferation of NSCLC cells by down-regulating the expression of EGFR, thereby inhibiting the downstream signaling pathway AKT/mTOR and c-Raf/ERK1/2. In addition, 8e also markedly reduces migration and induces the apoptosis of A549 and H1299 cells. results based on a lung cancer cell transplanted xenograft mouse model have further shown that 8e blocks A549 tumor growth without any significant hepatotoxicity or nephrotoxicity. These results indicate the high potential value of 8e as a candidate for treating NSCLC.
肺癌是发病率和死亡率最高的疾病之一。我们之前的研究发现，一种新型双胍衍生物，1-正庚基-5-(3,4-二氟苯基)双胍(8e)在非小细胞肺癌(NSCLC)细胞系A549中显示出优异的抗增殖活性。然而，其潜在机制仍不清楚。在本研究中，我们分析了8e对NSCLC细胞系的影响，并探讨了8e引起的细胞死亡机制。从我们的数据中，我们发现8e以剂量依赖的方式显著降低细胞活性并抑制A549和H1299细胞的集落形成。有趣的是，在用慢病毒载体沉默EGFR后，8e的这种抑制作用显著降低。相反，在A549和H1299中过表达EGFR后,8e对肿瘤细胞的杀伤力增加。同时，我们观察到8e抑制EGFR及其两个重要下游信号通路AKT/mTOR和c-Raf/ERK1/2的表达，并显著降低EGF诱导的EGFR通路的激活。因此，结果表明8e通过下调EGFR的表达来抑制NSCLC细胞的增殖，从而抑制下游信号通路AKT/mTOR和c-Raf/ERK1/2。此外，8e还显著减少A549和H1299细胞的迁移并诱导其凋亡。基于肺癌细胞移植异种移植小鼠模型的结果进一步表明，8e可阻断A549肿瘤生长，且无任何明显的肝毒性或肾毒性。这些结果表明8e作为治疗NSCLC的候选药物具有很高的潜在价值。
