β-elemene enhances the antitumor activity of erlotinib by inducing apoptosis through AMPK and MAPK pathways in TKI-resistant H1975 lung cancer cells

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) significantly improve the outcome of non-small-cell lung cancer (NSCLC) patients with EGFR mutations, however, most TKI-treated patients will develop resistance to TKIs. β-elemene, extracted from Curcuma aromatica Salisb., has been widely used to treat various malignant tumors, including TKI-resistant NSCLC, but, the effects and the molecular mechanisms remain unclear. In this study, the NCI-H1975 cell line harboring double mutations L858R/T790M was treated with varying concentrations of β-elemene and/or erlotinib. The effects of β-elemene on cell proliferation, migration, apoptosis, and the expression of relevant proteins of NCI-H1975 cells were evaluated. The results revealed that β-elemene significantly inhibited the growth, colony formation capacity, wound healing ability of NCI-H1975 cells, and improved the sensitivity of NCI-H1975 cells to erlotinib. Compared with erlotinib alone, β-elemene plus erlotinib significantly promoted the apoptosis of NCI-H1975 cells, accompanied by the down-regulated expression of P-mTOR, P-EGFR, CHOP proteins and up-regulated expression of P-AMPKα and Bax proteins. Taken together, these findings demonstrate that β-elemene suppresses the proliferation and migration of TKI-resistant H1975 cells, and enhances the antitumor activity of erlotinib by inducing apoptosis through AMPK and MAPK pathways in TKI-resistant H1975 lung cancer cells, indicating that β-elemene is a promising anti-cancer therapeutic candidate for TKI-resistant NSCLC.