Peruvoside is a new Src inhibitor that suppresses NSCLC cell growth and motility by downregulating multiple Src-EGFR-related pathways
Abstract Background The tyrosine kinase Src plays an essential role in the progression of many cancers and is involved in several signalling pathways regulated by EGFR. To improve the efficacy of lung cancer treatments, this study aimed to identify novel compounds that can disrupt the Src-EGFR interaction to inhibit lung cancer progression and are less dependent on the EGFR mutation status than other compounds. Methods We used Src pY419 ELISA as the drug-screening platform to screen a compound library of more than 400 plant active ingredients and identified peruvoside as a candidate Src-EGFR crosstalk inhibitor. Human Non-small cell lung cancer cell lines (A549, PC9, PC9/gef, H3255 and H1975) with different EGFR statuses were used to perform cell cytotoxicity and proliferation assays after peruvoside or dasatinib treatment. Src and Src-related protein expression was evaluated by western blotting in peruvoside-treated A549, H3255 and H1975 cells. The effects of peruvoside on cancer cell function were assessed in A549 cells. The synergistic effects of gefitinib and peruvoside were assessed by CI-isobologram analysis in gefitinib-resistant cell lines. The efficacy of peruvoside in vivo was determined using nude mice subjected to compound or vehicle treatments. Results Peruvoside significantly suppressed the phosphorylation of Src, EGFR, and STAT3 in a dose- and time-dependent manner and somewhat suppressed their protein expression. Cell function assays revealed that peruvoside also inhibited the proliferation, invasion, migration, and colony formation of lung cancer cells in vitro and tumour growth in vivo. Furthermore, peruvoside sensitised gefitinib-resistant tumour cells (A549, PC9/gef and H1975) to gefitinib treatment, indicating that it 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 multiple proteins, including Src, PI3K, JNK, Paxillin, p130cas, and EGFR. Conclusions Our findings suggest that peruvoside suppresses Non-small cell lung cancer malignancy by downregulating multiple Src-related pathways and may help develop new anticancer drugs and therapeutic strategies for lung cancer in the future.