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.

Preliminary Study on Phytochemical Constituents and Biological Activities of Essential Oil from Myriactis nepalensis Less.

“…Another important compound in M. nepalensis essential oil is β-elemene, a noncytotoxic broad-spectrum antitumor drug utilized in Chinese traditional medicine (TCM) for more than 20 years to treat various cancer types, including lung, gastric, cervical, breast, liver, and bladder cancers, etc., including tyrosine kinase inhibitor (TKI)-resistant non-small-cell lung cancer [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. Apart from its anticancer activity, β-elemene also possesses antioxidative and anti-inflammatory activities [ 54 , 55 ].…”

“…Unfortunately, the essential oil showed a cytotoxic effect on HL-7702 cells, with IC 50 values of 19.14 ± 0.63 μg/mL. The cytotoxic activity of M. nepalensis essential oil could be attributed to the above-mentioned main compounds, as their cytotoxic effects on numerous cell lines have been widely reported [ 24 , 25 , 26 , 27 , 28 , 41 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 91 ].…”

β-Elemene alleviates cisplatin resistance in oral squamous cell carcinoma cell via inhibiting JAK2/STAT3 pathway in vitro and in vivo

“…Numerous studies have revealed that β-Ele could modulate multiple molecular pathways such as ERK1/2, PI3K/Akt/mTOR, ROS-MPAK, JAK/STAT3 involved in carcinogenesis [ 22 , 23 , 30 ]. It is reported that JAK/STAT3 signaling pathway plays critical roles in progression of many human solid tumors such as breast cancer [ 31 ], ovarian cancer [ 32 ] and OSCC [ 33 ].…”

β-Elemene Enhance the Cisplatin Sensitivity of Oral Squamous Cell Carcinoma via Inhibiting JAK2/STAT3 Pathway in Vitro and in Vivo

“…Numerous studies have revealed that β-Ele could modulate multiple molecular pathways such as ERK1/2, PI3K/Akt/mTOR, ROS-MPAK, JAK/STAT3 involved in carcinogenesis [21,22,29]. It is reported that JAK/STAT3 signaling pathway plays critical roles in progression of many human solid tumors such as breast cancer [30], ovarian cancer [31] and OSCC [32].…”