title: Effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway.
abstract: OBJECTIVE
  Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and is used to reduce cancer-induced osteolysis. We reported previously that ZOL delayed both the growth and pain progression of bone metastases from hepatocellular carcinoma. The present study was designed to evaluate the effects of ZOL on hepatoma cell lines and the molecular mechanisms of such effects.
  
  
  METHODS
  Cell viability assay, scratch assay, immunohistochemistry, Western blotting, and flow cytometry analysis were performed using Huh7 and HepG2 cells treated with and without ZOL.
  
  
  RESULTS
  ZOL reduced cell growth in a dose-dependent manner and prevented cell migration when used at a concentration exceeding 10 μM. Immunohistochemistry showed that the inhibitory effects of ZOL on hepatoma cell progression was not due to the suppression of Ras and RhoA expression but due to inhibition of their translocation from the cytosol to the cell membrane, which terminates mevalonate pathway. Immunoblotting and flow cytometry showed that ZOL inhibited the mitogen-activated protein kinase pathway (MAPK) and induced apoptosis of hepatoma cells.
  
  
  CONCLUSIONS
  Our results indicated that ZOL prevented cell growth and metastasis based on direct antitumor effects in hepatoma cells. The use of ZOL could not only suppress the progression to bone metastatic lesions but also prevented growth of primary hepatocellular carcinoma.
authors.affiliation: Department of Medicine and Molecular Science, Hiroshima University, Hiroshima, Japan.
authors.forename: Yohji
authors.initials: Y
authors.lastname: Honda
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.forename: Eisuke
authors.initials: E
authors.lastname: Murakami
authors.forename: Niu
authors.initials: N
authors.lastname: Shi
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Kawaoka
authors.forename: Daiki
authors.initials: D
authors.lastname: Miki
authors.forename: Masataka
authors.initials: M
authors.lastname: Tsuge
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiraga
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.forename: Michio
authors.initials: M
authors.lastname: Imamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Aikata
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000517:prevention & control / Q000556:secondary*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000473:pathology; D003864:Depression, Chemical; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D008798:Mevalonic Acid / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D020928:Mitogen-Activated Protein Kinases; D008798:Mevalonic Acid
keywords: Ras and RhoA; apoptosis; bisphosphonate; zoledronic acid