Heat-processed neoginseng, KG-135, down-regulates G1 Cyclin-dependent kinase through the proteasome-mediated pathway in HeLa cells.

High temperature heat treatment of ginseng (Panax ginseng, C.A. Meyer) generates KG-135 (heat-processed neoginseng) which contains a mixture of three major ginseng saponins, ginsenosides Rk1, Rg3 and Rg5. Ginsenosides, particularly of the diol-type including Rk1, Rg3 and Rg5, have been shown to induce cell growth arrest in various cell types of human cancer. Herein, we report that KG-135 is able to arrest the cell cycle in human cervix adenocarcinoma HeLa cells. KG-135 arrests cells at the G1 phase of the cell cycle with an IC50 value of 69 microg/ml. The G1 phase arrest is associated with down-regulation of Cyclin D1/Cdk4 and Cyclin B1/Cdc2 activities in cells after treatment with KG-135. Furthermore, down-regulation of G1 Cyclin-dependent kinase activities is kinetically well related to the decreased intracellular protein levels of these kinases. In addition, the decrease in the levels of Cyclin D1/Cdk4 and Cyclin B1, but not of Cdc2, is similarly prevented by co-treatment of cells with MG-132, a potent proteasome inhibitor. Thus, the KG-135-induced arrest of the cell cycle at G1 phase in HeLa cells represents a novel mechanism that involves proteasome-mediated degradation of the Cyclins (Cyclin D1 and B1) and Cdk4 proteins.