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Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells.
Biochem Pharmacol. 2006 May 14; 71(10):1435-48.BP

Abstract

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+Show Affiliations

Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, 12200 Berlin, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16530734

Citation

Höpfner, Michael, et al. "Blockade of IGF-1 Receptor Tyrosine Kinase Has Antineoplastic Effects in Hepatocellular Carcinoma Cells." Biochemical Pharmacology, vol. 71, no. 10, 2006, pp. 1435-48.
Höpfner M, Huether A, Sutter AP, et al. Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. Biochem Pharmacol. 2006;71(10):1435-48.
Höpfner, M., Huether, A., Sutter, A. P., Baradari, V., Schuppan, D., & Scherübl, H. (2006). Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. Biochemical Pharmacology, 71(10), 1435-48.
Höpfner M, et al. Blockade of IGF-1 Receptor Tyrosine Kinase Has Antineoplastic Effects in Hepatocellular Carcinoma Cells. Biochem Pharmacol. 2006 May 14;71(10):1435-48. PubMed PMID: 16530734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. AU - Höpfner,Michael, AU - Huether,Alexander, AU - Sutter,Andreas P, AU - Baradari,Viola, AU - Schuppan,Detlef, AU - Scherübl,Hans, Y1 - 2006/03/10/ PY - 2005/12/21/received PY - 2006/01/26/revised PY - 2006/02/03/accepted PY - 2006/3/15/pubmed PY - 2006/5/26/medline PY - 2006/3/15/entrez SP - 1435 EP - 48 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 71 IS - 10 N2 - 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. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/16530734/Blockade_of_IGF_1_receptor_tyrosine_kinase_has_antineoplastic_effects_in_hepatocellular_carcinoma_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(06)00092-X DB - PRIME DP - Unbound Medicine ER -