title: Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) affects an increasing number of people worldwide. The poor survival rate of patients with HCC is manifested by an aggressive and metastatic phenotype, as well as a poor response to common therapeutic strategies. The purpose of this study was to evaluate the efficacy of nanoliposomal C6-ceramide as an antineoplastic agent in an in vivo model of human HCC.
  
  
  METHODS
  The growth-arresting and pro-apoptotic properties of nanoliposomal C6-ceramide were first evaluated in vitro in human SK-HEP-1 cells by assessing cellular viability, caspase 3/7 activity, annexin-V expression, DNA fragmentation, cell cycle distribution and AKT phosphorylation. SK-HEP-1 cells were then engrafted subcutaneously into athymic nude mice and nanoliposomal C6-ceramide was administered by tail vein injection. Tumour size was monitored over time, followed by excision of tumours to evaluate tumour vascularisation, proliferation, apoptosis and cellular signalling.
  
  
  RESULTS
  Nanoliposomal C6-ceramide, but not ghost (no ceramide) nanoliposomes, induced apoptotic cell death of SK-HEP-1 cells in vitro, concomitant with an accumulation of cells in the G₂ phase of the cell cycle and decreased phosphorylation of AKT. Systemic administration of nanoliposomal C6-ceramide to mice engrafted with SK-HEP-1 tumours reduced tumour vascularisation and proliferation, induced tumour cell apoptosis, decreased phosphorylation of AKT and ultimately blocked tumour growth.
  
  
  CONCLUSIONS
  These studies show that nanoliposomal ceramide is an efficacious antineoplastic agent for the treatment of in vitro and in vivo models of human HCC.
authors.affiliation: Departments of Pharmacology and of Cellular and Molecular Physiology, Hershey, PA 17033-0858, USA.
authors.forename: Hephzibah Rani S
authors.initials: HR
authors.lastname: Tagaram
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Divittore
authors.forename: Brian M
authors.initials: BM
authors.lastname: Barth
authors.forename: James M
authors.initials: JM
authors.lastname: Kaiser
authors.forename: Diego
authors.initials: D
authors.lastname: Avella
authors.forename: Eric T
authors.initials: ET
authors.lastname: Kimchi
authors.forename: Yixing
authors.initials: Y
authors.lastname: Jiang
authors.forename: Harriet C
authors.initials: HC
authors.lastname: Isom
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Staveley-O'Carroll
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002518:Ceramides / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008081:Liposomes; D008113:Liver Neoplasms / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D008081:Liposomes; C101954:N-caproylsphingosine; D051057:Proto-Oncogene Proteins c-akt