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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are used to treat non-small-cell lung cancer (NSCLC), harboring an EGFR-activating mutation. However, acquired resistance to these treatments emerges after a few years. One of causes of resistance to EGFR-TKIs is a high level of c-Met amplification or c-Met protein overexpression/hyperactivation. Therefore, combination therapy with EGFR-TKIs and a c-Met inhibitor is thought to be effective treatment for patients with NSCLC resistance carrying c-Met amplification and/or protein hyperactivation. Ephedra Herb is a crude drug and is used in Japan as a component in many Kampo formulae. We previously reported that Ephedra Herb extract (EHE) inhibits HGF-induced phosphorylation of c-Met by preventing c-Met tyrosine kinase activity. Thus, we investigated the combination effect of EHE and erlotinib, an EGFR-TKI, on growth of H1993 cells, an erlotinib-resistant NSCLC cell line with overexpression of c-Met. The EHE and erlotinib combination proved to be effective in suppression of the growth of H1993 xenograft tumors and on inhibition of proliferation of H1993 cells, suggesting that EHE is effective in rescuing NSCLC cells from erlotinib resistance. Moreover, EHE not only inhibited the phosphorylation of c-Met, but also downregulated the expression of c-Met by facilitating clathrin-mediated endocytosis and lysosomal degradation of c-Met. EHE also promoted downregulation of the expression of EGFR and phosphorylation of EGFR. Ephedrine alkaloids-free Ephedra Herb extract (EFE) had the same effects as EHE, and the 40% MeOH fraction from EFE, which mainly contained the high-molecular mass condensed tannins, decreased the expression levels of c-Met, pMet, EGFR, and pEGFR to almost the same level as EFE. These results suggest that recovery from resistance to erlotinib by EHE is derived from the high-molecular mass condensed tannins and that EHE may be suitable for treatment of c-Met-overexpressing NSCLC with resistance to EGFR-TKIs.

evidence-based complementary and alternative medicine

Effect of Ephedra Herb on Erlotinib Resistance in c-Met-Overexpressing Non-Small-Cell Lung Cancer Cell Line, H1993, through Promotion of Endocytosis and Degradation of c-Met