Combination of icotinib and wogonin induces apoptosis and autophagy to overcome acquired resistance in lung cancer harbouring EGFR T790M mutation
نویسندگان
چکیده
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used as targeted chemotherapeutic drugs in the treatment of advanced non-small cell lung cancer (NSCLC). However, acquired resistance against TKIs caused by T790M mutation of EGFR has become a major clinical problem. In this study, we assessed whether the combination of wogonin, a natural monoflavonoid, and icotinib could overcome T790Mmediated acquired resistance to icotinib, a novel EGFR-TKI with preclinical and clinical activity. Cell counting kit-8 assay showed that wogonin and icotinib caused timeand dose-dependent growth inhibition of NCI-H1975, which is a T790M-positive cell line. Wogonin plus icotinib combination produced a more pronounced growth inhibition and significantly increased the percentage of early apoptotic cells and cleavage of caspase 3 compared to cells treated with wogonin or icotinib alone. Furthermore, the number of intracellular autophagosomes, LC3B-I conversion to LC3B-II, and Beclin 1 expression after treatment with wogonin and icotinib combination were higher than those after treatment with wogonin or icotinib alone. The combined treatment with wogonin and icotinib upregulated the levels of phosphorylated mTOR. The suppression of mTOR phosphorylation by 3-methyladenine weakened the effects of wogonin and icotinib on cell autophagy and apoptosis. In conclusion, the combination of icotinib and wogonin exerted synergistic inhibitory effects on cell proliferation, and could induce apoptosis and autophagy in EGFR T790Mmutated lung cancer. The combination of icotinib and wogonin could become a potential strategy to overcome the acquired resistance to EGFR-TKIs in T790M mutant lung cancer.
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