title: Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and WNT/β-catenin pathways.
abstract: OBJECTIVE
  The aim of this study is to find synergistic effect using FH535 and sorafenib by targeting the RAS/RAF/MAPK and WNT/β-catenin pathways.
  
  
  METHODS
  3H-Thymidine incorporation assays were performed to address Huh7 and liver cancer stem cell (LCSC) inhibition using FH535 and sorafenib, alone and in combination. Calcusyn analysis was used to calculate the combination index (CI). A western blot assay was performed to check for potential targets.
  
  
  RESULTS
  FH535 and sorafenib caused inhibition of Huh7 and LCSC. Combination therapy was significantly better than monotherapy in inhibition of HuH7. Combination with sorafenib and FH535 was found to be synergistic in inhibition of LCSC with a CI of less than 1. The western blot assay demonstrated enhanced cleaved poly (ADP-ribose) polymerase (PARP) and inhibition of cyclin D1, B-cell lymphoma 2 (Bcl2), survivin and cellular myelocytomatosis oncogene (c-MYC).
  
  
  CONCLUSIONS
  FH535 and sorafenib combination produced synergistic effect on inhibition of HCC and LCSC. Our study demonstrated that FH535 can induce apoptosis in these two different hepatocellular carcinoma (HCC) cell lines.
authors.affiliation: 800 Rose Street, Room C453, Lexington, Kentucky 40536-0293, U.S.A. rgeda2@uky.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Galuppo
authors.forename: Erin
authors.initials: E
authors.lastname: Maynard
authors.forename: Malay
authors.initials: M
authors.lastname: Shah
authors.forename: Michael F
authors.initials: MF
authors.lastname: Daily
authors.forename: Changguo
authors.initials: C
authors.lastname: Chen
authors.forename: Brett T
authors.initials: BT
authors.lastname: Spear
authors.forename: Roberto
authors.initials: R
authors.lastname: Gedaly
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology; D000077022:Survivin; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D048490:raf Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C575430:FH535; D051034:Inhibitor of Apoptosis Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D000077022:Survivin; D009536:Niacinamide; D000077157:Sorafenib; D011065:Poly(ADP-ribose) Polymerases; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Hepatocellular carcinoma; PI-103; PKI-587; RAS/RAF/MAPK; epidermal growth factor; liver cancer stem cells; mTOR complex 1; mTOR complex 2; rapamycin; sorafenib