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

• Published in: Cell death & disease Vol. 11; no. 8; p. 621
• Main Authors: Huang, Qi, Zhang, Hui, Bai, Li Ping, Law, Betty Yuen Kwan, Xiong, Haoming, Zhou, Xiaobo, Xiao, Riping, Qu, Yuan Qing, Mok, Simon Wing Fai, Liu, Liang, Wong, Vincent Kam Wai
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 14.08.2020; Nature Publishing Group UK
• Subjects: Adenylate Kinase - metabolism; AMP; AMP-activated protein kinase; Animals; Antitumor activity; Apoptosis - drug effects; ATP; Biomarkers, Tumor - metabolism; Body weight; Cancer; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell Respiration - drug effects; Cyclin-Dependent Kinases - metabolism; Cyclins - metabolism; Down-Regulation - drug effects; Energy; Energy balance; Energy metabolism; Energy Metabolism - drug effects; Enzymes; Ginseng; Ginsenosides; Ginsenosides - chemistry; Ginsenosides - pharmacology; Glycolysis; Glycolysis - drug effects; Humans; Isomers; Kinases; Lactic acid; Lung cancer; MAP Kinase Signaling System - drug effects; Metabolism; Metastases; Metastasis; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms - enzymology; Neoplasms - metabolism; Neoplasms - pathology; Phosphopyruvate hydratase; Phosphopyruvate Hydratase - metabolism; S Phase - drug effects; S-Phase Kinase-Associated Proteins - metabolism; Stathmin - metabolism; Toxicity; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02881-4

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.