1-n-heptyl-5-(3, 4-difluorophenyl) biguanide inhibits non-small cell lung cancer cell growth by downregulating the EGFR signaling pathways.

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.