title: Icariin potentiates the antitumor activity of gemcitabine in gallbladder cancer by suppressing NF-κB.
abstract: OBJECTIVE
  Gemcitabine has been increasingly prescribed for the treatment of gallbladder cancer. However, the response rate is low. The aim of this study is to determine whether icariin, a flavonoid isolated from Epimedi herba, could potentiate the antitumor activity of gemcitabine in gallbladder cancer.
  
  
  METHODS
  Human gallbladder carcinoma cell lines GBC-SD and SGC-996 were tested. Cell proliferation and apoptosis were analyzed using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related molecules was detected with Western blotting. Caspase-3 activity was analyzed using colorimetric assay, and NF-κB activity was measured with ELISA. A gallbladder cancer xenograft model was established in female BALB/c (nu/nu) mice. The mice were intraperitoneally administered gemcitabine (125 mg/kg) in combination with icariin (40 mg/kg) for 2 weeks.
  
  
  RESULTS
  Icariin (40-160 μg/mL) dose-dependently suppressed cell proliferation and induced apoptosis in both GBC-SD and SGC-996 cells, with SGC-996 cells being less sensitive to the drug. Icariin (40 μg/mL) significantly enhanced the antitumor activity of gemcitabine (0.5 μmol/L) in both GBC-SD and SGC-996 cells. The mice bearing gallbladder cancer xenograft treated with gemcitabine in combination with icariin exhibited significantly smaller tumor size than the mice treated with either drug alone. In GBC-SD cells, icariin significantly inhibited both the constitutive and gemcitabine-induced NF-κB activity, enhanced caspase-3 activity, induced G(0)-G(1) phase arrest, and suppressed the expression of Bcl-2, Bcl-xL and surviving proteins.
  
  
  CONCLUSIONS
  Icariin, by suppressing NF-κB activity, exerts antitumor activity, and potentiates the antitumor activity of gemcitabine in gallbladder cancer. Combined administration of gemcitabine and icariin may offer a better therapeutic option for the patients with gallbladder cancer.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital, Nanjing Medical University, China.
authors.forename: Dian-cai
authors.initials: DC
authors.lastname: Zhang
authors.forename: Jin-long
authors.initials: JL
authors.lastname: Liu
authors.forename: Yong-bin
authors.initials: YB
authors.lastname: Ding
authors.forename: Jian-guo
authors.initials: JG
authors.lastname: Xia
authors.forename: Guo-yu
authors.initials: GY
authors.lastname: Chen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D005704:Gallbladder / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D016328:NF-kappa B; D003841:Deoxycytidine; C056599:icariin; D000093542:Gemcitabine