Suppression on metastasis by rhubarb through modulation on MMP-2 and uPA in human A549 lung adenocarcinoma: An ex vivo approach

• Published in: Journal of ethnopharmacology Vol. 133; no. 2; pp. 426 - 433
• Main Authors: Shia, Chi-Sheng, Suresh, Govindan, Hou, Yu-Chi, Lin, Yu-Chin, Chao, Pei-Dawn Lee, Juang, Shin-Hun
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 27-01-2011; Amsterdam; New York: Elsevier; Elsevier
• Subjects: adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - secondary; Administration, Oral; animal models; Animals; anticarcinogenic activity; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Base Sequence; biochemical pathways; Biological and medical sciences; Cell Line, Tumor; cell motility; Cell Movement - drug effects; cultured cells; DNA Primers - genetics; Down-Regulation - drug effects; enzyme activity; Ethnopharmacology; General pharmacology; Humans; In Vitro Techniques; JNK Mitogen-Activated Protein Kinases - metabolism; lung neoplasms; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Male; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; mechanism of action; Medical sciences; medicinal plants; Medicine, Chinese Traditional; Metabolic event; metabolites; metalloproteinases; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; MMP-2; NF-kappa B - metabolism; oral administration; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phytotherapy; Plant Extracts - administration & dosage; Plant Extracts - pharmacology; Plants, Medicinal - chemistry; post-translational modification; Rats; Rats, Sprague-Dawley; Rheum - chemistry; Rheum hybridum; Rhubarb; Taiwan; Traditional Chinese medicine; transcription (genetics); transcription factors; uPA; Urokinase-Type Plasminogen Activator - metabolism; Asia; China; Taiwan; Traditional Chinese medicine; Metabolic event; Rhubarb; Metastasis; MMP-2; uPA; u-Plasminogen activator; Metalloendopeptidases; Bronchopulmonary adenocarcinoma; Bronchopulmonary; Medicinal plant; Ex vivo; Folk medicine; Bronchus disease; Human; Lung disease; Serine endopeptidases; Enzyme; Respiratory disease; Pharmacognosy; Malignant tumor; Metabolism; Peptidases; Plant origin; Hydrolases; Pharmacokinetics; Cancer
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2010.10.020

The aim of this study is to determine and identify the possible molecular mechanisms of anti-cancer effect of rhubarb under the physiologically achievable concentrations by using an ex vivo approach.
Rats were orally administered rhubarb decoction and then serum metabolites were extracted, prepared and characterized to assay for the following in vitro study. The MTT assay, zymography analysis, wound healing assay, RT-PCR, and Western blot analysis were used to reveal molecular events of rhubarb metabolites in this study. Experimental metastasis model was used to investigate the in vivo anti-metastatic efficacy of rhubarb.
Our results demonstrated that cell line mobility was strongly inhibited and the enzymatic activity of MMP-2 decreased following culture with the rhubarb serum metabolite in human lung adenocarcinoma A549 cells. Further experiments demonstrated that the downregulation of MMP-2 enzymatic activity act through both transcriptional and post-translational mechanisms. NF-κB/c-Jun and uPA were observed involving in the inhibition of MMP-2 transcription and post-translational modification, respectively, in A549 cells treated with rhubarb serum metabolite. Further animal experiments demonstrated a significant reduction in lung metastatic colonies in rhubarb-treated mice, suggesting that rhubarb contain enriched active components that block cancer metastasis.
Our studies, both in vitro and in vivo, clearly demonstrated the anti-tumor effect of rhubarb in an experimental setting of achievable physiological concentrations and also provide possible molecular mechanisms of anti-metastatic mechanisms by rhubarb treatment.