title: Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib.
abstract: As the result of an increasing incidence and a prevalent therapy resistance of hepatocellular carcinoma (HCC), there is a strong need for novel strategies to enhance treatment responses in HCC. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising anticancer drug because it can selectively induce apoptosis in cancer cells, but not in healthy cells. Nevertheless, most tumor cells show TRAIL resistance, emphasizing the requirement for apoptosis-sensitizing agents and TRAIL molecules with improved tumor specificity. In this study, we employed a recombinant TRAIL molecule, in which three TRAIL protomers were expressed as a single polypeptide chain (scTRAIL), and a novel TRAIL variant, in which scTRAIL was additionally fused to an antibody fragment recognizing epidermal growth factor receptor (EGFR) to improve its HCC-targeting properties. We analyzed the proapoptotic effects of both TRAIL versions in combination with the proteasome inhibitor bortezomib (BZB) in hepatoma cells and primary human hepatocytes as well as in intact explants from HCC and healthy liver tissue. We demonstrate that EGFR-targeted TRAIL in combination with BZB induced significantly higher caspase activation and cell death in hepatoma cells, but not in primary hepatocytes. Importantly, when incubated with fresh liver explants, the combination of EGFR-targeted TRAIL and BZB displayed selective cytotoxicity for HCC, but not for tumor-free liver tissue, which could even be verified in liver explants from the same individuals. Unlike nontargeted TRAIL, EGFR-targeted TRAIL combined with BZB exerted no toxicity in liver tissues from nonalcoholic fatty liver disease patients.
  
  
  CONCLUSIONS
  EGFR-targeted TRAIL reveals increased antitumor activity toward HCC without inducing toxicity to tumor-free liver tissue and might therefore represent a promising novel strategy for HCC treatment.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Wahl
authors.forename: Martin
authors.initials: M
authors.lastname: Siegemund
authors.forename: Frank
authors.initials: F
authors.lastname: Lehner
authors.forename: Florian
authors.initials: F
authors.lastname: Vondran
authors.forename: Andreas
authors.initials: A
authors.lastname: Nüssler
authors.forename: Florian
authors.initials: F
authors.lastname: Länger
authors.forename: Till
authors.initials: T
authors.lastname: Krech
authors.forename: Roland
authors.initials: R
authors.lastname: Kontermann
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfizenmaier
authors.forename: Heike
authors.initials: H
authors.lastname: Bantel
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D066246:ErbB Receptors / Q000627:therapeutic use*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D058990:Molecular Targeted Therapy; D011719:Pyrazines / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib; D066246:ErbB Receptors