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The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours.
Endocr Relat Cancer. 2006 Mar; 13(1):135-49.ER

Abstract

Gastrointestinal neuroendocrine tumours (NET) represent a heterogeneous tumour entity. The anti-neoplastic therapy of advanced NET disease is still unsatisfactory and innovative therapeutic approaches are needed. As NET frequently express insulin-like growth factors (IGFs) and their receptors (IGFR), known to promote survival, oncogenic transformation, tumour growth and spreading, the inhibition of the IGF/IGF-receptor system may offer possibilities for novel targeted treatment strategies of NET. Here, we studied the anti-neoplastic effects of an inhibition of the IGF-I receptor (IGF-1R) signalling in NET cells by the novel IGF-1R tyrosine kinase (TK) inhibitor NVP-AEW541, whose anti-neoplastic potency has not yet been tested in NET disease. Using two human NET cell lines with different growth characteristics, we demonstrated that NVP-AEW541 dose-dependently inhibited the proliferation of NET cells by inducing apoptosis and cell cycle arrest. Anti-neoplastic effects of NVP-AEW541 were also detected in primary cultures of human neuroendocrine gastrointestinal tumours. Apoptosis was characterized by activation of the apoptotic key enzyme, caspase-3, as well as by detection of changes in the expression of the pro- and anti-apoptotic proteins, BAX and Bcl-2, after NVP-AEW541 treatment. Cell cycle was arrested at the G1/S checkpoint. The anti-neoplastic effects of NVP-AEW541 involved the inactivation of ERK1/2. Induction of immediate cytotoxicity did not account for the anti-neoplastic effects of NVP-AEW541, as shown by measurement of lactate dehydrogenase release. Moreover, additive anti-neoplastic effects were observed when NVP-AEW541 was combined with cytostatics such as doxorubicin or the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin. This is the first report on the induction of apoptosis and cell cycle arrest by the IGF-1R-TK inhibitor, NVP-AEW541, in NET cells. The inhibition of the IGF/IGFR system appears to be a promising novel approach for future treatment strategies of NET disease.

Authors+Show Affiliations

Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Hindenburgdamm 30, 12200 Berlin, Germany.No 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

16601284

Citation

Höpfner, Michael, et al. "The Insulin-like Growth Factor Receptor 1 Is a Promising Target for Novel Treatment Approaches in Neuroendocrine Gastrointestinal Tumours." Endocrine-related Cancer, vol. 13, no. 1, 2006, pp. 135-49.
Höpfner M, Baradari V, Huether A, et al. The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours. Endocr Relat Cancer. 2006;13(1):135-49.
Höpfner, M., Baradari, V., Huether, A., Schöfl, C., & Scherübl, H. (2006). The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours. Endocrine-related Cancer, 13(1), 135-49.
Höpfner M, et al. The Insulin-like Growth Factor Receptor 1 Is a Promising Target for Novel Treatment Approaches in Neuroendocrine Gastrointestinal Tumours. Endocr Relat Cancer. 2006;13(1):135-49. PubMed PMID: 16601284.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours. AU - Höpfner,Michael, AU - Baradari,Viola, AU - Huether,Alexander, AU - Schöfl,Christof, AU - Scherübl,Hans, PY - 2006/4/8/pubmed PY - 2006/7/11/medline PY - 2006/4/8/entrez SP - 135 EP - 49 JF - Endocrine-related cancer JO - Endocr Relat Cancer VL - 13 IS - 1 N2 - Gastrointestinal neuroendocrine tumours (NET) represent a heterogeneous tumour entity. The anti-neoplastic therapy of advanced NET disease is still unsatisfactory and innovative therapeutic approaches are needed. As NET frequently express insulin-like growth factors (IGFs) and their receptors (IGFR), known to promote survival, oncogenic transformation, tumour growth and spreading, the inhibition of the IGF/IGF-receptor system may offer possibilities for novel targeted treatment strategies of NET. Here, we studied the anti-neoplastic effects of an inhibition of the IGF-I receptor (IGF-1R) signalling in NET cells by the novel IGF-1R tyrosine kinase (TK) inhibitor NVP-AEW541, whose anti-neoplastic potency has not yet been tested in NET disease. Using two human NET cell lines with different growth characteristics, we demonstrated that NVP-AEW541 dose-dependently inhibited the proliferation of NET cells by inducing apoptosis and cell cycle arrest. Anti-neoplastic effects of NVP-AEW541 were also detected in primary cultures of human neuroendocrine gastrointestinal tumours. Apoptosis was characterized by activation of the apoptotic key enzyme, caspase-3, as well as by detection of changes in the expression of the pro- and anti-apoptotic proteins, BAX and Bcl-2, after NVP-AEW541 treatment. Cell cycle was arrested at the G1/S checkpoint. The anti-neoplastic effects of NVP-AEW541 involved the inactivation of ERK1/2. Induction of immediate cytotoxicity did not account for the anti-neoplastic effects of NVP-AEW541, as shown by measurement of lactate dehydrogenase release. Moreover, additive anti-neoplastic effects were observed when NVP-AEW541 was combined with cytostatics such as doxorubicin or the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, fluvastatin. This is the first report on the induction of apoptosis and cell cycle arrest by the IGF-1R-TK inhibitor, NVP-AEW541, in NET cells. The inhibition of the IGF/IGFR system appears to be a promising novel approach for future treatment strategies of NET disease. SN - 1351-0088 UR - https://www.unboundmedicine.com/medline/citation/16601284/The_insulin_like_growth_factor_receptor_1_is_a_promising_target_for_novel_treatment_approaches_in_neuroendocrine_gastrointestinal_tumours_ L2 - https://erc.bioscientifica.com/doi/10.1677/erc.1.01090 DB - PRIME DP - Unbound Medicine ER -