(-)-Epigallocatechin-3-gallate derivatives combined with cisplatin exhibit synergistic inhibitory effects on non-small-cell lung cancer cells

Jing Wang; Peiyuan Sun; Qi Wang; Pan Zhang; Yuna Wang; Chengting Zi; Xuanjun Wang; Jun Sheng

doi:10.1186/s12935-019-0981-0

(-)-Epigallocatechin-3-gallate derivatives combined with cisplatin exhibit synergistic inhibitory effects on non-small-cell lung cancer cells

Cancer Cell Int. 2019 Oct 14:19:266. doi: 10.1186/s12935-019-0981-0. eCollection 2019.

Authors

Jing Wang^#^{1

2

3}, Peiyuan Sun^#^{1

3}, Qi Wang¹, Pan Zhang¹, Yuna Wang^{1

3}, Chengting Zi^{1

2}, Xuanjun Wang^{1

2

4}, Jun Sheng^{1

2

4}

Affiliations

¹ 1Key Laboratory of Pu-er Tea Science, Ministry of Education, Yunnan Agricultural University, Kunming, Yunnan China.
² 2College of Science, Yunnan Agricultural University, Kunming, 650201 Yunnan China.
³ 3College of Food Science and Technology, Yunnan Agricultural University, Kunming, Yunnan China.
⁴ State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Kunming, Yunnan China.

^# Contributed equally.

Abstract

Background: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. The inhibition of epidermal growth factor receptor (EGFR) signaling by tyrosine kinase inhibitors or monoclonal antibodies plays a key role in NSCLC treatment. Unfortunately, these treatment strategies are limited by eventual resistance and cell lines with differential EGFR status. Therefore, new therapeutic strategies for NSCLC are urgently required.

Methods: To improve the stability and absorption of (-)-epigallocatechin-3-gallate (EGCG), we synthesized a series of EGCG derivatives. The antitumor activities of EGCG derivatives with or without cisplatin were investigated in vitro and vivo. Cell proliferation, cell cycle distribution and apoptosis were measured in NSCLC cell lines and in vivo in a NCI-H441 xenograft model.

Results: We found that the EGCG derivatives inhibited cell viability and colony formation, caused cell cycle redistribution, and induced apoptosis. More importantly, the combination of the EGCG derivative and cisplatin led to increased growth inhibition, caused cell cycle redistribution, and enhanced the apoptosis rate compared to either compound alone. Consistent with the experiments in vitro, EGCG derivatives plus cisplatin significantly reduced tumor growth.

Conclusions: The combination treatment was found to inhibit the EGFR signaling pathway and decrease the expression of p-EGFR, p-AKT, and p-ERK in vitro and vivo. Our results suggest that compound 3 is a novel potential compound for NSCLC patients.

Keywords: Cisplatin; EGCG derivatives; EGFR; NSCLC; Synthesis.