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

Jue Wang; Cong Xu; Ying Chen; Le Shao; Ting Li; Xingxing Fan; Lili Yu; Ruonan Zhang; Bi Chen; Hongwei Chen; Xinbing Sui; Elaine Lai-Han Leung; Qibiao Wu

doi:10.7150/jca.53382

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

J Cancer. 2021 Feb 22;12(8):2285-2294. doi: 10.7150/jca.53382. eCollection 2021.

Authors

Jue Wang^{1

2}, Cong Xu^{1

2}, Ying Chen^{3

4}, Le Shao⁵, Ting Li^{1

2}, Xingxing Fan^{1

2}, Lili Yu^{1

2}, Ruonan Zhang^{1

2

6

7}, Bi Chen^{1

2

6

7}, Hongwei Chen^{3

8}, Xinbing Sui^{6

7}, Elaine Lai-Han Leung^{1

2}, Qibiao Wu^{1

2

9

10}

Affiliations

¹ Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China.
² State Key Laboratory of Quality Research in Chinese Medicines (Macau University of Science and Technology), Taipa, Macau, China.
³ Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau, China.
⁴ GCP center, the Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China.
⁵ The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.
⁶ Department of Medical Oncology, Holistic Integrative Oncology Institutes and Holistic Integrative Cancer Center of Traditional Chinese and Western Medicine, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
⁷ Department of Cancer Pharmacology, Holistic Integrative Pharmacy Institutes, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
⁸ School of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen, Guangdong, China.
⁹ Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangzhou, China.
¹⁰ University Hospital, Macau University of Science and Technology Foundation, Taipa, Macau, China.

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.

Keywords: AMPK; EGFR-mutated; NSCLC; TKI-resistant; apoptosis; mechanisms; β-elemene.