Source:http://linkedlifedata.com/resource/pubmed/id/16601284
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
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| pubmed:dateCreated |
2006-4-7
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| pubmed:abstractText |
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.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibiotics, Antineoplastic,
http://linkedlifedata.com/resource/pubmed/chemical/CASP3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Doxorubicin,
http://linkedlifedata.com/resource/pubmed/chemical/Drug Combinations,
http://linkedlifedata.com/resource/pubmed/chemical/Fatty Acids, Monounsaturated,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxymethylglutaryl-CoA...,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/L-Lactate Dehydrogenase,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/NVP-AEW541,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrroles,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, IGF Type 1,
http://linkedlifedata.com/resource/pubmed/chemical/fluvastatin
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| pubmed:status |
MEDLINE
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| pubmed:month |
Mar
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| pubmed:issn |
1351-0088
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
13
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
135-49
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:16601284-Antibiotics, Antineoplastic,
pubmed-meshheading:16601284-Apoptosis,
pubmed-meshheading:16601284-Caspase 3,
pubmed-meshheading:16601284-Caspases,
pubmed-meshheading:16601284-Cell Cycle,
pubmed-meshheading:16601284-Doxorubicin,
pubmed-meshheading:16601284-Drug Combinations,
pubmed-meshheading:16601284-Fatty Acids, Monounsaturated,
pubmed-meshheading:16601284-Gastrointestinal Neoplasms,
pubmed-meshheading:16601284-Humans,
pubmed-meshheading:16601284-Hydroxymethylglutaryl-CoA Reductase Inhibitors,
pubmed-meshheading:16601284-Indoles,
pubmed-meshheading:16601284-L-Lactate Dehydrogenase,
pubmed-meshheading:16601284-Mitogen-Activated Protein Kinase 1,
pubmed-meshheading:16601284-Mitogen-Activated Protein Kinase 3,
pubmed-meshheading:16601284-Neuroendocrine Tumors,
pubmed-meshheading:16601284-Pyrimidines,
pubmed-meshheading:16601284-Pyrroles,
pubmed-meshheading:16601284-Receptor, IGF Type 1,
pubmed-meshheading:16601284-Signal Transduction,
pubmed-meshheading:16601284-Tumor Cells, Cultured
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| pubmed:year |
2006
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| pubmed:articleTitle |
The insulin-like growth factor receptor 1 is a promising target for novel treatment approaches in neuroendocrine gastrointestinal tumours.
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| pubmed:affiliation |
Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Hindenburgdamm 30, 12200 Berlin, Germany.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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