title: 20(S)-Ginsenoside Rg3 is a novel inhibitor of autophagy and sensitizes hepatocellular carcinoma to doxorubicin.
abstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. High mortality from HCC is mainly due to widespread prevalence and the lack of effective treatment, since systemic chemotherapy is ineffective, while the targeted agent Sorafenib extends median survival only briefly. The steroidal saponin 20(S)-ginsenoside Rg3 from Panax ginseng C.A. Meyer is proposed to chemosensitize to various therapeutic drugs through an unknown mechanism. Since autophagy often serves as cell survival mechanism in cancer cells exposed to chemotherapeutic agents, we examined the ability of Rg3 to inhibit autophagy and chemosensitize HCC cell lines to doxorubicin in vitro. We show that Rg3 inhibits late stage autophagy, possibly through changes in gene expression. Doxorubicin-induced autophagy plays a protective role in HCC cells, and therefore Rg3 treatment synergizes with doxorubicin to kill HCC cell lines, but the combination is relatively nontoxic in normal liver cells. In addition, Rg3 was well-tolerated in mice and synergized with doxorubicin to inhibit tumor growth in HCC xenografts in vivo. Since novel in vivo inhibitors of autophagy are desirable for clinical use, we propose that Rg3 is such a compound, and that combination therapy with classical chemotherapeutic drugs may represent an effective therapeutic strategy for HCC treatment.
authors: Department of Biochemistry and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon.
authors: Dong-Gun
authors: DG
authors: Kim
authors: College of Medicine, Inha University, Incheon.
authors: Kyung Hee
authors: KH
authors: Jung
authors: Department of Biochemistry and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon.
authors: Da-Gyum
authors: DG
authors: Lee
authors: Department of Biochemistry and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon.
authors: Jung-Ho
authors: JH
authors: Yoon
authors: Department of Biochemistry and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon.
authors: Kyeong Sook
authors: KS
authors: Choi
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors: Sung Won
authors: SW
authors: Kwon
authors: Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
authors: Han-Ming
authors: HM
authors: Shen
authors: Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado.
authors: Michael J
authors: MJ
authors: Morgan
authors: College of Medicine, Inha University, Incheon.
authors: Soon-Sun
authors: SS
authors: Hong
authors: Department of Biochemistry and Department of Biomedical Sciences, Ajou University School of Medicine, Suwon.
authors: You-Sun
authors: YS
authors: Kim
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D036145:Ginsenosides / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male
chemical_list: D000903:Antibiotics, Antineoplastic; D036145:Ginsenosides; C097367:ginsenoside Rg3; D004317:Doxorubicin