title: Antimetastatic activity of honokiol in osteosarcoma.
abstract: BACKGROUND
  Metastasizing osteosarcoma has a mean 5-year survival rate of only 20% to 30%. Therefore, novel chemotherapeutics for more effective treatment of this disease are required.
  
  
  METHODS
  The antineoplastic activity of honokiol, which was demonstrated previously in numerous malignancies, was studied in vivo in C3H mice subcutaneously injected with syngeneic β-galactosidase bacterial gene (lacZ)-expressing LM8 osteosarcoma (LM8-lacZ) cells. In vitro cytotoxic effects of honokiol were investigated in 8 human and 2 murine osteosarcoma cell lines with different in vivo metastatic potential.
  
  
  RESULTS
  Seven days after subcutaneous flank injection of LM8-lacZ cells, daily intraperitoneal treatment of mice with 150 mg/kg honokiol reduced the number of micrometastases in the lung by 41% and reduced the number of macrometastases in the lung and liver by 69% and 80%, respectively, compared with control. Primary tumor growth was not inhibited. In osteosarcoma cell lines, honokiol inhibited the metabolic activity with a half-maximal concentration (IC(50) ) between 8.0 μg/mL and 16 μg/mL. Cyclosporin A partially reversed the inhibition of metabolic activity in LM8-lacZ cells. Cell proliferation and wound healing migration of LM8-lacZ cells were inhibited by honokiol with an IC(50) between 5.0 μg/mL and 10 μg/mL. Higher concentrations caused rapid cell death, which was distinct from necrosis, apoptosis, or autophagy but was associated with swelling of the endoplasmic reticulum, cytoplasmic vacuolation, and morphologically altered mitochondria.
  
  
  CONCLUSIONS
  Honokiol exhibited prominent antimetastatic activity in experimental osteosarcoma and caused rapid cell death in vitro that was unrelated to necrosis, apoptosis, or autophagy. The authors concluded that honokiol has considerable potential for the treatment of metastasizing osteosarcoma.
authors.affiliation: Laboratory for Orthopedic Research, Department of Orthopedics, University of Zurich, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Steinmann
authors.forename: Denise K
authors.initials: DK
authors.lastname: Walters
authors.forename: Matthias J E
authors.initials: MJ
authors.lastname: Arlt
authors.forename: Ingo J
authors.initials: IJ
authors.lastname: Banke
authors.forename: Urs
authors.initials: U
authors.lastname: Ziegler
authors.forename: Bettina
authors.initials: B
authors.lastname: Langsam
authors.forename: Jack
authors.initials: J
authors.lastname: Arbiser
authors.forename: Roman
authors.initials: R
authors.lastname: Muff
authors.forename: Walter
authors.initials: W
authors.lastname: Born
authors.forename: Bruno
authors.initials: B
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D017705:Lignans; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols