title: A hepatoprotective Lindera obtusiloba extract suppresses growth and attenuates insulin like growth factor-1 receptor signaling and NF-kappaB activity in human liver cancer cell lines.
abstract: BACKGROUND
  In traditional Chinese and Korean medicine, an aqueous extract derived from wood and bark of the Japanese spice bush Lindera obtusiloba (L.obtusiloba) is applied to treat inflammations and chronic liver diseases including hepatocellular carcinoma. We previously demonstrated anti-fibrotic effects of L.obtusiloba extract in hepatic stellate cells. Thus, we here consequently examine anti-neoplastic effects of L.obtusiloba extract on human hepatocellular carcinoma (HCC) cell lines and the signaling pathways involved.
  
  
  METHODS
  Four human HCC cell lines representing diverse stages of differentiation were treated with L.obtusiloba extract, standardized according to its known suppressive effects on proliferation and TGF-β-expression. Beside measurement of proliferation, invasion and apoptosis, effects on signal transduction and NF-κB-activity were determined.
  
  
  RESULTS
  L.obtusiloba extract inhibited proliferation and induced apoptosis in all HCC cell lines and provoked a reduced basal and IGF-1-induced activation of the IGF-1R signaling cascade and a reduced transcriptional NF-κB-activity, particularly in the poorly differentiated SK-Hep1 cells. Pointing to anti-angiogenic effects, L.obtusiloba extract attenuated the basal and IGF-1-induced expression of hypoxia inducible factor-1α, vascular endothelial growth factor, peroxisome proliferator-activated receptor-γ, cyclooxygenase-2 and inducible nitric oxide synthase.
  
  
  CONCLUSIONS
  The traditional application of the extract is confirmed by our experimental data. Due to its potential to inhibit critical receptor tyrosine kinases involved in HCC progression via the IGF-1 signaling pathway and NF-κB, the standardized L.obtusiloba extract should be further analysed for its active compounds and explored as (complementary) treatment option for HCC.
authors.affiliation: Department of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Freise
authors.forename: Martin
authors.initials: M
authors.lastname: Ruehl
authors.forename: Ulrike
authors.initials: U
authors.lastname: Erben
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.forename: Daniel
authors.initials: D
authors.lastname: Seehofer
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Kim
authors.forename: Wolfram
authors.initials: W
authors.lastname: Trowitzsch-Kienast
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stroh
authors.forename: Martin
authors.initials: M
authors.lastname: Zeitz
authors.forename: Rajan
authors.initials: R
authors.lastname: Somasundaram
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D027443:Lindera; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D008517:Phytotherapy; D024301:Plant Bark; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014934:Wood
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D010936:Plant Extracts; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D017526:Receptor, IGF Type 1