Article first published online: 8 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 2, pages 625–636, February 2013
How to Cite
Wahl, K., Siegemund, M., Lehner, F., Vondran, F., Nüssler, A., Länger, F., Krech, T., Kontermann, R., Manns, M. P., Schulze-Osthoff, K., Pfizenmaier, K. and Bantel, H. (2013), Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib. Hepatology, 57: 625–636. doi: 10.1002/hep.26082
Potential conflict of interest: Drs. Kontermann and Pfizenmaier consult for and received grants from Biontech.
This study was supported by the Deutsche Forschungsgemeinschaft (SFB Transregio 77, SFB 685, and SFB 773) and BMBF (project no.: 0315-280A; FORSYS-Partner “Predictive Cancer Therapy”).
- Issue published online: 5 FEB 2013
- Article first published online: 8 JAN 2013
- Accepted manuscript online: 18 SEP 2012 06:12AM EST
- Manuscript Accepted: 4 SEP 2012
- Manuscript Received: 19 MAY 2012
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. Conclusion: 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. (HEPATOLOGY 2013)