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Molecular mechanisms of ginsenoside Rh2-mediated G(1) growth arrest and apoptosis in human lung adenocarcinoma A549 cells.

Cheng CC, Yang SM, Huang CY, Chen JC, Chang WM, Hsu SL

Department of Education and Research, Taichung Veterans General Hospital, No. 160, Section 3, Chung-Gang Road, Taichung, 407, Taiwan.

Ginsenoside Rh2 (Rh2), a purified ginseng saponin, has been shown to have antiproliferative effects in certain cancer cell types. However, the molecular mechanisms by which Rh2 affects cell growth and death have not been fully clarified. In this study, the antiproliferative effects of Rh2 in human lung adenocarcinoma A549 cells were investigated. Treatment of A549 cells with 30 mug/ml Rh2 resulted in G(1) phase arrest, followed by progression to apoptosis. This Rh2-mediated G(1) arrest was accompanied by the downregulation of the protein levels and kinase activities of cyclin-D1, cyclin-E and Cdk6, and the upregulation of pRb2/p130. In addition, Rh2-induced apoptosis was confirmed by the TUNEL assay and DNA fragmentation analysis. Administration of Rh2 caused an increase in the expression levels of TRAIL-RI (DR4) death receptor but did not alter the levels of other death receptors or Bcl-2 family molecules. Furthermore, the Rh2-induced apoptosis was significantly inhibited by DR4:Fc fusion protein, which inhibits TRAIL-DR4-mediated apoptosis. In addition, caspases-2, -3 and -8 were strongly activated upon Rh2 treatment. Inhibitors of caspases-2, -3 and -8 markedly prevented the cell death induced by Rh2, and inhibitor of caspase-8 significantly inhibited the activation of caspases-2, -3 and -8. These observations indicate that multiple G(1)-related cell cycle regulatory proteins are regulated by Rh2 and contribute to Rh2-induced G(1) growth arrest. The increase in the expression levels of DR4 death receptor may play a critical role in the initiation of Rh2-induced apoptosis, and the activation of the caspase-8/caspase-3 cascade acts as the executioner of the Rh2-induced death process.

Published 17 March 2005 in Cancer Chemother Pharmacol.
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