title: Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy.
abstract: OBJECTIVE
  Recently, the anti-apoptotic Mcl-1 protein has been reported as a resistance factor in various types of cancer. Here we investigated the presence of Mcl-1 protein in hepatocellular carcinoma (HCC) tissues and its potential role as a molecular drug target for HCC therapy.
  
  
  METHODS
  HCC specimens of 149 patients were examined by immunohistochemistry for Mcl-1 expression. Antisense oligonucleotides (ASO) targeting Mcl-1 were evaluated as monotherapy and in combination with cisplatin in the HCC cell lines HepG2 and Snu398. Protein regulation, cell viability, and apoptosis were assessed by western blotting, cell counting, and FACS analysis.
  
  
  RESULTS
  Mcl-1 protein is overexpressed in 51% of all cases irrespective of underlying disease. Targeting Mcl-1 by ASO specifically downregulated Mcl-1 protein expression and led to significant dose and time dependent single agent activity in HCC cells characterized by increased apoptosis and decreased cell viability. No significant target regulation or cell death was observed for control oligonucleotide treatment. Upon combination with cisplatin, Mcl-1 ASO revealed a significant chemosensitizing effect.
  
  
  CONCLUSIONS
  Mcl-1 is overexpressed in half of HCC-tissues. ASO targeting Mcl-1 revealed a prominent single agent and chemosensitizing activity against HCC in vitro. Targeting Mcl-1 might qualify as a promising novel approach in HCC therapy.
authors.affiliation: Section of Experimental Oncology/Molecular Pharmacology, Department of Clinical Pharmacology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sieghart
authors.forename: Doris
authors.initials: D
authors.lastname: Losert
authors.forename: Sabine
authors.initials: S
authors.lastname: Strommer
authors.forename: Daniel
authors.initials: D
authors.lastname: Cejka
authors.forename: Katharina
authors.initials: K
authors.lastname: Schmid
authors.forename: Susanne
authors.initials: S
authors.lastname: Rasoul-Rockenschaub
authors.forename: Martin
authors.initials: M
authors.lastname: Bodingbauer
authors.forename: Richard
authors.initials: R
authors.lastname: Crevenna
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002452:Cell Count; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012334:RNA, Neoplasm