Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells.

Abstract

UNLABELLED:

Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. Due to very poor 5-year-survival new therapeutic approaches are mandatory. Most HCCs express insulin-like growth factors and their receptors (IGF-R). As IGF-1R-mediated signaling promotes survival, oncogenic transformation and tumor growth and spread, it represents a potential target for innovative treatment strategies of HCC. Here we studied the antineoplastic effects of inhibiting IGF-1R signaling in HCC cells by the novel IGF-1R tyrosine kinase inhibitor NVP-AEW541.

METHODS AND RESULTS:

NVP-AEW541 induced a time- and dose-dependent growth inhibition in the human hepatoblastoma and hepatocellular carcinoma cell lines SK-Hep-1, Hep-3B, Hep-G2 and Huh-7. Measurement of LDH-release showed that the antineoplastic effect of NVP-AEW541 was not due to cytotoxicity. Instead NVP-AEW541 induced apoptosis as evidenced by both caspase-3 and -8 activation as well as by apoptosis-specific morphological and mitochondrial changes. In addition, nuclear degradation was monitored by DNA-laddering. NVP-AEW541-treatment suppressed the expression of the antiapoptotic proteins Bcl-2 and survivin, while the expression of the proapoptotic protein BAX was stimulated in a dose-dependent manner. Moreover, NVP-AEW541 arrested the cell cycle at the G1/S checkpoint. When NVP-AEW541 was combined with cytotoxic chemotherapy or with a specific epidermal growth factor receptor antibody additive antiproliferative effects were observed.

INTERPRETATION:

Inhibition of IGF-1R tyrosine kinase (IGF-1R-TK) by NVP-AEW541 induces growth inhibition, apoptosis and cell cycle arrest in human HCC cell lines without accompanying cytotoxicity. Thus, IGF-1R-TK inhibition may be a promising novel treatment approach in HCC.

• Authors: Michael Höpfner, Alexander Huether, Andreas P Sutter, Viola Baradari, Detlef Schuppan, Hans Scherübl
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 71 Issue 10 Pg. 1435-48 (May 14 2006) ISSN: 0006-2952 [Print] England
• PMID: 16530734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drug Combinations
• Enzyme Inhibitors
• NVP-AEW541
• Pyrimidines
• Pyrroles
• RNA, Messenger
• Receptor, IGF Type 1

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, enzymology, pathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA Fragmentation
• Dose-Response Relationship, Drug
• Drug Combinations
• Enzyme Inhibitors (pharmacology)
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• Liver Neoplasms (drug therapy, enzymology, pathology)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• RNA, Messenger (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, genetics, metabolism)