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

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.