title: Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation Huanglian-Jiedu decoction in human hepatocellular carcinoma.
abstract: BACKGROUND
  An oriental medicinal formulation, Huanglian Jiedu Decoction (HLJDD), has been well documented in few Traditional Chinese Medicine Classics 1300 years ago for treatment of heat and dampness-related diseases. Its effect is well accepted in Asian community, including China, Japan and Korea. Recent studies have postulated HLJDD as a regimen for cancer treatment, especially liver cancer, but the underlying mechanism is unknown. The aim of this study was to examine the suppressive effect of HLJDD on the growth of hepatocellular carcinoma (HCC) and its possible underlying mechanism.
  
  
  METHODS
  Chemical composition of HLJDD was analyzed by high performance liquid chromatography. The tumor suppressive effect of HLJDD was determined on both HCC cells and xenograft model. Nascent protein synthesis was detected with Click-IT protein labeling technology; protein expression was determined by immunoblotting and imunnohistochemical analysis.
  
  
  RESULTS
  Quality analysis revealed that HLJDD of different batches is consistent in both chemical composition and bioactivities. HLJDD inhibited HCC cell proliferation at its non-toxic doses, and suppressed growth and angiogenesis in xenografted murine model. HLJDD suppressed the synthesis of nascent protein via inactivation of eEF2 without deregulating the translation initiation factors. The major components in HLJDD, geniposide, berberine and baicalin, additively act on eEF2, and contributed to the responsible activity. HLJDD-activated eEF2 kinase (eEF2K) led to eEF2 inactivation, and activation of AMPK signaling may be responsible for the eEF2K induction. Blocked AMPK activity in HLJDD-treated HCC cells attenuated eEF2K activation as well as the inhibitory effect of the formula. In nutrient deprived HCC cells with inactivated eEF2, the inhibitory effect of HLJDD in tumor cell expansion was interfered.
  
  
  CONCLUSIONS
  Our results indicate that HLJDD has potential in blocking HCC progression with involvement of eEF2 inhibition.
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China. Electronic address: yfeng@hku.hk.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Feng
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Hor-Yue
authors.initials: HY
authors.lastname: Tan
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Fan
authors.initials: F
authors.lastname: Cheung
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Ming
authors.initials: M
authors.lastname: Hong
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Lixing
authors.initials: L
authors.lastname: Lao
authors.affiliation: Laboratory of Pharmacobiology and Therapeutics, Faculty of Pharmacy, Meijo University, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagamatsu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D001599:Berberine / Q000032:analysis / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D004365:Drugs, Chinese Herbal / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000032:analysis / Q000494:pharmacology; D006801:Humans; D039823:Iridoids / Q000032:analysis / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D008517:Phytotherapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D039823:Iridoids; C061676:oren gedoku to; D001599:Berberine; C007835:geniposide; C038044:baicalin; C517689:EEF2K protein, human; D054736:Elongation Factor 2 Kinase
keywords: AMPK; Hepatocellular carcinoma; Huanglian Jiedu decoction; Nascent protein synthesis; eEF2