The structure-activity relationship (SAR) of and novel molecular mechanisms for ginsenosides as anticancer agents

1921

Ginseng has been used for thousands of years in Asian countries for its wide spectrum of health effects, and is known for its tonic, immunomodulatory, adaptogenic and anti-aging activities. The use of ginseng and related products in cancer prevention and treatment also has been explored for many years in Western countries. Many of its medicinal effects and pharmacological actions are attributed to ginsenosides that include more than twenty family members with varying biological activities. Multiple mechanisms of action for ginsenosides have been suggested, including anti-inflammatory and antioxidant effects, induction of apoptosis, regulation of gene expression and modulation of cell proliferation. However, the underlying molecular mechanisms and the SAR of ginsenosides are not fully understood. This study was undertaken to investigate the SAR of selected ginsenosides for their anti-cancer effects. Among 12 ginsenosides tested, two newly identified compounds, 25-OH-PPD and 25-OCH3-PPD, were shown to be most active based on their effects on cell viability, apoptosis, cell cycle distribution, and cell proliferation in human breast cancer MCF7 (p53^wt/wt) and MDA-MB-468 (p53^mt/mt) cells and prostate cancer LNCaP (p53^wt/wt) and PC3 (p53^null) cells. For example, 25-OCH3-PPD had the most potent anti-cancer activities, having IC50 values of 13.5, 18.2, 12.0 and 5.6 microM in MCF7, MDA-MB-468, LNCaP, and PC3 cells, respectively. In contrast, other compounds had 10-100-fold lower activities. In a dose- and structure-dependent manner, effective ginsenosides arrested cancer cells in the G1 phase. This arrest was accompanied by down-regulation of the MDM2 oncogene and activation of tumor suppressors such as p53 and p21^WAF1/CIP1. In conclusion, several ginsenosides, especially 25-OH-PPD and 25-OCH3-PPD, exert their anticancer activity through inducing apoptosis and G1 arrest and inhibiting proliferation in cancer cells, regardless of p53 status. Their down-regulation of the MDM2 oncogene has not been previously reported, and is a novel molecular mechanism for their anticancer effects. These results provide a basis for further development of ginsenoside analogs as novel agents in cancer prevention and therapy.