Document Detail


Nonsteroidal anti-inflammatory drugs inhibit growth of human neuroendocrine tumor cells via G1 cell-cycle arrest.
MedLine Citation:
PMID:  14566837     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Therapeutic options to inhibit growth of human NETs of the GEP system are limited. Since NSAIDs might provide an antiproliferative treatment alternative with acceptable toxicity, we examined the effects of different NSAIDs on growth and survival in a representative set of human GEP NET cell lines. Growth and apoptosis were determined based on cell numbers, cell-cycle analyses, kinase assays, DNA fragmentation and PARP cleavage. Expression of COX and cell cycle-regulatory molecules was examined by immunoblotting and reporter gene assays. Depending on the drug and cell line investigated, NSAID treatment resulted in profound growth inhibition of GEP NET cells. Growth-inhibitory effects were achieved with either COX-2 selective (NS398) or unselective (indomethacin, sulindac) compounds. Cell-cycle analyses documented a G1 arrest in NSAID-treated GEP NET populations. In addition, 100 microM sulindac or indomethacin induced apoptosis. All 3 COX inhibitors prevented CDK-2 activation. In parallel to the NSAID-mediated reduction of CDK-2 activity, p21(cip-1) promoter activity and cellular p21(cip-1) levels increased and p21(cip-1) was sequestered into CDK-2 complexes. Thus, the G1 arrest likely resulted from p21(cip-1)-dependent inhibition of CDK-2 activity. At therapeutically relevant concentrations, sulindac significantly reduced GEP NET cell numbers, whereas IFN-alpha and octreotide remained ineffective. The extent of growth inhibition in GEP NETs was comparable to the antiproliferative effects of sulindac in established NSAID-sensitive cell models. NSAIDs acted as potent antiproliferative agents in GEP NET cells via G1 cell-cycle arrest and might therefore offer a therapeutic alternative to current treatment modalities.
Authors:
Katharina M Detjen; Martina Welzel; Bertram Wiedenmann; Stefan Rosewicz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  107     ISSN:  0020-7136     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-10-20     Completed Date:  2004-02-18     Revised Date:  2007-07-24    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  844-53     Citation Subset:  IM    
Copyright Information:
Copyright 2003 Wiley-Liss, Inc.
Affiliation:
Medizinische Klinik mit Schwerpunkt Hepatologie, Gastroenterologie, Endokrinologie und Stoffwechsel, Universitätsklinikum Charité, Campus Virchow Klinikum, Humboldt Universität zu Berlin, Berlin, Germany.
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MeSH Terms
Descriptor/Qualifier:
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Apoptosis / drug effects
Carcinoma, Neuroendocrine
Cell Cycle / drug effects*
Cell Division / drug effects*
Cyclooxygenase Inhibitors / pharmacology*
DNA Fragmentation
Flow Cytometry
G1 Phase / drug effects
Humans
Indomethacin / pharmacology
Sulindac / pharmacology
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Cyclooxygenase Inhibitors; 38194-50-2/Sulindac; 53-86-1/Indomethacin

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