Abstract
The tyrosine kinase Src plays an essential role in the progression of many cancers and is involved in several epidermal growth factor receptor (EGFR)-mediated signalling pathways. To improve the efficacy of lung cancer treatments, this study aimed to identify novel compounds that can disrupt the Src-EGFR interaction and that are less dependent on EGFR status with wild-type and mutations than other compounds. We used the Src pY419 ELISA as the platform to screen a compound library of more than 400 plant-derived active ingredients and identified peruvoside as a candidate Src-EGFR crosstalk inhibitor. The effects of peruvoside were evaluated by western blotting, cell function assays, combination Index (CI)-isobologram analyses and in vivo experiments. Peruvoside significantly suppressed the phosphorylation of Src, EGFR, and signal transducer and activator of transcription 3 (STAT3) in a dose- and time-dependent manner and somewhat suppressed their protein expression. Cell function assays revealed that peruvoside inhibited the proliferation, invasion, migration, and colony formation of lung cancer cells in vitro and tumour growth in vivo. Furthermore, peruvoside sensitized gefitinib-resistant tumour cells (A549, PC9/gef and H1975) to gefitinib treatment, indicating that peruvoside may exert synergistic effects when used in combination with established therapeutic agents. Our data also demonstrated that the inhibitory effects of peruvoside on lung cancer progression might be attributed to its ability to regulate Src, phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinase (JNK), Paxillin, p130cas, and EGFR. Our findings suggest that peruvoside suppresses non-small-cell lung carcinoma (NSCLC) malignancy by downregulating multiple Src-related pathways and could serve as a potential base molecule for developing new anticancer drugs and therapeutic strategies for lung cancer.