Abstract
As the main active ingredients of Panax ginseng, ginsenosides possess numerous bioactivities. Epidermal growth factor receptor (EGFR) was widely used as a valid target in anticancer therapy. Herein, the EGFR targeting activities of 20(S)-ginsenoside Rh2 (20(S)-Rh2) and the relationship of their structure-activity were investigated. Homogeneous time-resolved fluorescence assay showed that 20(S)-Rh2 significantly inhibited the activity against EGFR kinase. 20(S)-Rh2 was confirmed to effectively inhibited cell proliferation in a dose-dependent manner by MTT assay. Furthermore, quantitative real-time PCR and western blotting analysis revealed that 20(S)-Rh2 inhibited A549 cells growth via the EGFR-MAPK pathway. Meanwhile, 20(S)-Rh2 could promote cell apoptosis, block cell cycle, and reduce cell migration of A549 cells, respectively. In silico, the result suggested that both hydrophobic interactions and hydrogen-bonding interactions could contribute to stabilize their binding. Molecular dynamics simulation showed that the side chain sugar moiety of 20(S)-Rh2 was too flexible to be fixed at the active site of EGFR. Collectively, these findings suggested that 20(S)-Rh2 might serve as a potential EGFR tyrosine kinase inhibitor.
Highlights
Lung cancer is the leading cause of cancer death worldwide
Homogeneous timeresolved fluorescence (HTRF) assay is a homogeneous time-resolved assay that generates a signal by fluorescence resonance energy transfer (FRET) between the donor and acceptor molecules [27]
HTRF assay was taken to confirm that 20(S)-Rh2 significantly inhibited the activity of Epidermal growth factor receptor (EGFR) kinase
Summary
Non-small-cell lung cancer (NSCLC) contributes over 80% of lung cancer cases with a low 5-year survival rate [1]. The development of epidermal growth factor receptortyrosine kinase inhibitors (EGFR-TKIs) plays a key role in the targeted therapy of NSCLC. Epidermal growth factor receptor (EGFR) is considered a receptor tyrosine kinase with penetrating the cell membrane [2]. EGFR is composed of an extracellular ligand-binding region, a transmembrane region, and an intracellular tyrosine kinase region [3]. EGFR forms a dimer and the phosphate of ATP transfers into the tyrosine residue. It is well known that EGFR plays a key role in cell proliferation, apoptosis, and migration [6]. EGFR is confirmed to be dysregulated or overexpressed in various solid tumors and used as one of the valid targets in anticancer therapy [7, 8]
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