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Inhibitory effects of eupatilin on tumor invasion of human gastric cancer MKN-1 cells.

Abstract
Extracts of the whole herb of Artemisia asiatica Nakai (Asteraceae) are used in traditional oriental medicine to treat inflammation. Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone) is one of the pharmacologically active components found in A. asiatica, and has been shown to possess anti-tumoral effects in some malignancies, including gastric cancer. However, its anti-metastatic effect in gastric cancer is hardly known. In this study, anti-metastatic effect of eupatilin was investigated in the human gastric cancer cell line, MKN-1. Eupatilin inhibited MKN-1 growth in a dose- and a time-dependent manner, and induced apoptosis with a concomitant increase of caspase-3 activity. ELISA demonstrated that release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-8) was significantly reduced by eupatilin. And p-AKT and p-ERK (p44/42) was reduced. Expression level of β-catenin and integrin was reduced and p-GSKβ was increased. In transcription reporter system, the activity of the transcriptional factor, NF-κB, was reduced by eupatilin and the expression of p65 was down-regulated when MKN-1 cells were treated with eupatilin. Moreover, a zymography study revealed that this reduction in invasive potential resulted from a reduction in type IV collagenolytic (gelatinolytic) activity. The expressions of metalloproteinases (MMP-2 and MMP-9) were also reduced in MKN-1 cells treated with eupatilin. In vitro invasion assay, eupatilin inhibited MKN-1 penetrating reconstituted basement membrane barriers. These results suggest that eupatilin inhibits the MKN-1 gastric cancer cell proliferation via activation of caspase-3 and the metastatic potential of gastric cancer cells via down-regulation of NF-κB activity followed by reduction of pro-inflammatory cytokine-mediated MMPs expressions.
AuthorsByeong Bae Park, Jin sun Yoon, Eun shil Kim, Jiyoung Choi, Young woong Won, Jung hye Choi, Young Yiul Lee
JournalTumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 34 Issue 2 Pg. 875-85 (Apr 2013) ISSN: 1423-0380 [Electronic] Netherlands
PMID23292941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Drugs, Chinese Herbal
  • Flavonoids
  • Inflammation Mediators
  • NF-kappa B
  • RNA, Messenger
  • beta Catenin
  • eupatilin
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
Topics
  • Apoptosis (drug effects)
  • Blotting, Western
  • Caspase 3 (metabolism)
  • Cell Movement (drug effects)
  • Cell Proliferation
  • Drugs, Chinese Herbal
  • Enzyme-Linked Immunosorbent Assay
  • Flavonoids (pharmacology)
  • Humans
  • Inflammation Mediators (metabolism)
  • Matrix Metalloproteinase 2 (genetics, metabolism)
  • Matrix Metalloproteinase 9 (genetics, metabolism)
  • NF-kappa B (genetics, metabolism)
  • Neoplasm Invasiveness
  • Phosphorylation (drug effects)
  • Proto-Oncogene Proteins c-akt (genetics, metabolism)
  • RNA, Messenger (genetics)
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms (drug therapy, metabolism, pathology)
  • Tumor Cells, Cultured
  • beta Catenin (genetics, metabolism)

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