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Increased energy metabolism is responsible for supporting the abnormally upregulated proliferation and biosynthesis of cancer cells. The key cellular energy sensor AMP-activated protein kinase (AMPK) and the glycolytic enzyme alpha-enolase (α-enolase) have been identified as the targets for active components of ginseng. Accordingly, ginseng or ginsenosides have been demonstrated with their potential values for the treatment and/or prevention of cancer  via  the regulation of energy balance. Notably, our previous study demonstrated that the  R -form derivative of 20( R )-Rh2, 20( R )-Rh2E2 exhibits specific and potent anti-tumor effect via suppression of cancer energy metabolism. However, the uncertain pharmacological effect of  S -form derivative, 20( S )-Rh2E2, the by-product during the synthesis of 20( R )-Rh2E2 from parental compound 20( R/S )-Rh2 (with both  R - and  S -form), retarded the industrialized production, research and development of this novel effective candidate drug. In this study, 20( S )-Rh2E2 was structurally modified from pure 20( S )-Rh2, and this novel compound was directly compared with 20( R )-Rh2E2 for their in vitro and in vivo antitumor efficacy. Results showed that 20( S )-Rh2E2 effectively inhibited tumor growth and metastasis in a lung xenograft mouse model. Most importantly, animal administrated with 20( S )-Rh2E2 up to 320 mg/kg/day survived with no significant body weight lost or observable toxicity upon 7-day treatment. In addition, we revealed that 20( S )-Rh2E2 specifically suppressed cancer cell energy metabolism via the downregulation of metabolic enzyme α-enolase, leading to the reduction of lactate, acetyl-coenzyme (acetyl CoA) and adenosine triphosphate (ATP) production in Lewis lung cancer cells (LLC-1), but not normal cells. These findings are consistent to the results obtained from previous studies using a similar isomer 20( R )-Rh2E2. Collectively, current results suggested that 20( R / S )-Rh2E2 isomers could be the new and safe anti-metabolic agents by acting as the tumor metabolic suppressors, which could be generated from 20( R/S )-Rh2 in industrialized scale with low cost.

Novel ginsenoside derivative 20(S)-Rh2E2 suppresses tumor growth and metastasis in vivo and in vitro via intervention of cancer cell energy metabolism