Stereoisomer-Specific Anticancer Activities of Ginsenoside Rg3 and Rh2 in HepG2 Cells : Disparity in Cytotoxicity and Autophagy-Inducing Effects Due to 20(S)-Epimers

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  • Cheong Jong Hye
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
  • Kim Hyeryung
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
  • Hong Min Jee
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
  • Yang Min Hye
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
  • Kim Jung Wha
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
  • Yoo Hunseung
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
  • Yang Heejung
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
  • Park Jeong Hill
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
  • Sung Sang Hyun
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University
  • Kim Hong Pyo
    School of Pharmacy, Ajou University
  • Kim Jinwoong
    College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University

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  • Stereoisomer-Specific Anticancer Activities of Ginsenoside Rg3 and Rh2 in HepG2 Cells: Disparity in Cytotoxicity and Autophagy-Inducing Effects Due to 20(<i>S</i>)-Epimers

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Autophagy has been an emerging field in the treatment of hepatic carcinoma since anticancer therapies were shown to ignite autophagy in vitro and in vivo. Here we report that ginsenoside Rg3 and Rh2, major components of red ginseng, induce apoptotic cell death in a stereoisomer-specific fashion. The 20(S)-forms of Rg3 and Rh2, but not their respective 20(R)-forms, promoted cell death in a dose-dependent manner accompanied by downregulation of Bcl2 and upregulation of Fas, resulting in apoptosis of HepG2 cells with poly ADP ribose polymerase cleavage. The LD50 value [45 µM for Rg3(S), less than 10 µM for Rh2(S)] and gross morphological electron microscopic observation revealed more severe cellular damage in cells treated with Rh2(S) than in those treated with Rg3(S). Both Rg3(S) and Rh2(S) also induced autophagy when undergoing induced apoptosis. Inhibition of autophagy with lysosomotrophic agents significantly potentiated the cellular damage, implying a favorable switch of the cell fate to tumor cell death. Blocking intracellular calcium with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM) restored the cell death induced by both Rg3(S) and Rh2(S). Our results suggest that the 20(S)-forms of Rg3 and Rh2 in red ginseng possess more potent antitumor activity with autophagy than their 20(R)-forms via calcium-dependent apoptosis.

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