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.