The Effects of Artesunate on the Expression of EGFR and ABCG2 in A549 Human Lung Cancer Cells and a Xenograft Model

Hu Ma,Sheng Lin,Jian-Guo Sun,Xin-Xin Wang,Lei Wu,An-Mei Zhang,Quan Yao,Zheng-Tang Chen

doi:10.3390/molecules161210556

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Clinical and laboratory studies have suggested that multi-targeting approaches against neoplastic cells could help to increase patient survival and might reduce the emergence of cells that are resistant to single-target inhibitors. Artesunate (ART) is one of the most potent and rapidly acting antimalarial agents known, and it also exerts a profound cytotoxic activity toward cancer cells and reverses multi-drug resistance. In the present study, we found that artesunate inhibited NSCLC A549 cell growth and proliferation, induced apoptosis and suppressed tumor growth in a dose-dependent manner in A549 cells and a mouse xenograft model. Furthermore, artesunate down-regulated the expression of epidermal growth factor receptor (EGFR), Akt and ATP-binding cassette subfamily G member 2 (ABCG2) at the mRNA and protein levels in vitro and in vivo. In conclusion, artesunate is an effective anti-cancer drug that may enhance the effectiveness of other anticancer drugs and may reverse multi-drug resistance by suppressing the transcription of ABCG2, which inhibits drug efflux.

Highlights

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide
The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib (Tarceva) yield modest increases in survival when administered to NSCLC patients following chemotherapy
We found that the treatment of A549 cells and a xenograft tumor model with ART inhibited the phosphorylation of Akt and significantly down-regulated the mRNA and protein levels of ATP-binding cassette subfamily G member 2 (ABCG2)

Summary

Introduction

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Despite recent advances in the detection and treatment of lung cancer, the overall five years survival rate remains less than 15% in China. Most patients experience modest clinical benefits from standard platinum-based chemotherapy treatments, which are associated with a limited increase in overall survival [1]. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib (Tarceva) yield modest increases in survival when administered to NSCLC patients following chemotherapy. Studies have shown that a subset of NSCLC patients treated with these drugs enter remission [2,3]. This response is correlated with the presence of somatic activating mutations within the EGFR kinase domain [4,5]. Despite the efficacy of erlotinib and gefitinib in NSCLC patients with EGFR mutations, all patients will develop resistance to these agents

Results

Discussion

Conclusion