The Green Tea Polyphenol EGCG Potentiates the Antiproliferative Activity of c-Met and Epidermal Growth Factor Receptor Inhibitors in Non–small Cell Lung Cancer Cells

Abstract

Purpose Activation of the c-Met and epidermal growth factor receptors (EGFR) promotes growth and survival of non-small cell lung cancer (NSCLC). Specific receptor antagonists have demonstrated efficacy in the clinic; however, tumors often become resistant to these therapies. We have investigated the ability of (-)-epigallocatechin-3-gallate (EGCG) to inhibit cell proliferation, and c-Met receptor and EGFR kinase activation in several NSCLC cell lines. Experimental Design NSCLC cell lines with variable sensitivity to the EGFR antagonist erlotinib were studied. Cell growth was evaluated using MTS and colony formation assays. Kinase activation was assessed via western blot analysis. Experiments were conducted with EGCG, the EGFR antagonist erlotinib and the c-Met inhibitor SU11274. The antagonists were also tested in a xenograft model using SCID mice. Results EGCG inhibited cell proliferation in erlotinib sensitive and resistant cell lines, including those with c-Met overexpression and acquired resistance to erlotinib. The combination of erlotinib/EGCG resulted in greater inhibition of cell proliferation and colony formation than either agent alone. EGCG also completely inhibited ligand-induced c-Met phosphorylation and partially inhibited EGFR phosphorylation. The triple combination of EGCG/erlotinib/SU11274 resulted in a greater inhibition of proliferation than EGCG with erlotinib. Finally, the combination of EGCG and erlotinib significantly slowed the growth rate of H460 xenografts. Conclusion EGCG is a potent inhibitor of cell proliferation, independent of EGFR inhibition, in several NSCLC cell lines, including those resistant to both EGFR kinase inhibitors and those overexpressing c-Met. Therefore, EGCG might be a useful agent to study as an adjunct to other anti-cancer agents.

Role of Ku70 and Bax in epigallocatechin-3-gallate-induced apoptosis of A549 cells in vivo

“…In this study, we identified that EGCG, the major polyphenolic agent present in green tea, inhibited the growth of lung cancer A549 cells in vivo, which was consistent with previous studies indicating that EGCG inhibited growth and apoptosis in human lung, colon, gastric, prostate and mammary carcinoma (19)(20)(21)(22)(23). At present, a number of agents are used to clinically treat carcinoma, including cisplatin, gemcitabine and paclitaxel.…”

HGF-induced invasion by prostate tumor cells requires anterograde lysosome trafficking and activity of Na+-H+ exchangers

“…S6). Additionally, we examined the H1993 lung cancer cell line, in which Met is overexpressed due to MET gene amplification, causing constitutively active Met signaling (Milligan et al, 2009). We observed that lysosomes in H1993 cells were more peripherally localized under neutral pH culture conditions compared with DU145 and PC3 cells.…”

Green tea (−)-epigallocatechin-3-gallate inhibits HGF-induced progression in oral cavity cancer through suppression of HGF/c-Met

“…Recently, some studies showed that EGCG could inhibit the invasion and migration of human oral cancer cells through multiple mechanisms, possibly by the decreased production of MMP (matrix metalloproteinase)-2, MMP-9 and uPA or the demethylation effect on MMP inhibitors, such as RECK [19,20]. Also, EGCG has been reported to inhibit ligandinduced c-Met phosphorylation and potentially block invasive cancer growth [4,21]. Therefore, EGCG might be a useful agent to study as an adjunct to other anticancer agents.…”