title: Sorafenib and triptolide as combination therapy for hepatocellular carcinoma.
abstract: BACKGROUND
  Sorafenib is the only drug approved by the Food and Drug Administration for metastatic hepatocellular carcinoma (HCC). Triptolide, a diterpene triepoxide, exhibits antineoplastic properties in multiple tumor cell types. In this study, we examined the effects of these agents and their combination on HCC in vitro and in vivo models.
  
  
  METHODS
  HuH-7 and PLC/PRF/5 cells were treated with triptolide (50 nM), sorafenib (1.25 or 2.5 μM), or a combination of both. Cell viability assay (CCK-8), caspase 3&7 activation, and nuclear factor κB assays were performed. For in vivo studies, 40 mice were implanted with subcutaneous HuH7 tumors and divided into four treatment groups (n = 10); saline control, sorafenib 10 mg/kg PO daily (S), Minnelide (a prodrug of triptolide) 0.21 mg/kg intraperitoneally7 daily (M), and combination of both (C). Tumor volumes were assessed weekly.
  
  
  RESULTS
  The combination of triptolide and sorafenib was superior to either drug alone in inducing apoptosis and decreasing viability, whereas triptolide alone was sufficient to decrease nuclear factor κB activity. After 2 weeks of treatment, tumor growth inhibition rates were S = 59%, M = 84%, and C = 93%, whereas tumor volumes in control animals increased by 9-fold. When crossed over to combination treatment, control mice tumor growth volumes plateaued over the following 4 weeks.
  
  
  CONCLUSIONS
  The combination of sorafenib and triptolide is superior to single drug treatment in increasing cell death and apoptosis in vitro. Combining sorafenib with Minnelide inhibited tumor growth with greater efficacy than single-agent treatments. Importantly, in vivo combination treatment allowed for using a lesser dose of sorafenib (10 mg/kg), which is less than 10% of currently prescribed dose for HCC patients. Therefore, combination treatment could have translational potential in the management of HCC.
authors: Division of General Surgery, University of Minnesota, Minneapolis, MN.
authors: Osama A
authors: OA
authors: Alsaied
authors: Division of Basic and Translational Research, University of Minnesota, Minneapolis, MN.
authors: Veena
authors: V
authors: Sangwan
authors: Division of Basic and Translational Research, University of Minnesota, Minneapolis, MN.
authors: Sulagna
authors: S
authors: Banerjee
authors: Division of General Surgery, University of Minnesota, Minneapolis, MN.
authors: Tara C
authors: TC
authors: Krosch
authors: Division of Basic and Translational Research, University of Minnesota, Minneapolis, MN.
authors: Rohit
authors: R
authors: Chugh
authors: Division of Basic and Translational Research, University of Minnesota, Minneapolis, MN.
authors: Ashok
authors: A
authors: Saluja
authors: School of Medicine, University of Alabama, Birmingham, AL.
authors: Selwyn M
authors: SM
authors: Vickers
authors: Division of Surgical Oncology, Department of Surgery, University of Minnesota, Minneapolis, MN. Electronic address: jense893@umn.edu.
authors: Eric H
authors: EH
authors: Jensen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000008:administration & dosage; D004357:Drug Synergism; D004852:Epoxy Compounds / Q000008:administration & dosage; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010755:Organophosphates / Q000008:administration & dosage; D010616:Phenanthrenes / Q000008:administration & dosage; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011355:Prodrugs / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D012844:Sincalide / Q000378:metabolism; D000077157:Sorafenib; D057170:Translational Research, Biomedical; D023041:Xenograft Model Antitumor Assays
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D010755:Organophosphates; D010616:Phenanthrenes; D010671:Phenylurea Compounds; D011355:Prodrugs; C001899:triptolide; C579022:14-O-phosphonooxymethyltriptolide disodium salt; D009536:Niacinamide; D000077157:Sorafenib; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D012844:Sincalide