Document Detail


Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model.
MedLine Citation:
PMID:  16928983     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP-protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.
Authors:
Mårten Fryknäs; Linda Rickardson; Malin Wickström; Sumeer Dhar; Henrik Lövborg; Joachim Gullbo; Peter Nygren; Mats G Gustafsson; Anders Isaksson; Rolf Larsson
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of biomolecular screening     Volume:  11     ISSN:  1087-0571     ISO Abbreviation:  J Biomol Screen     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-08-24     Completed Date:  2006-11-01     Revised Date:  2011-05-23    
Medline Journal Info:
Nlm Unique ID:  9612112     Medline TA:  J Biomol Screen     Country:  United States    
Other Details:
Languages:  eng     Pagination:  457-68     Citation Subset:  IM    
Affiliation:
Department of Genetics and Pathology, Uppsala University, S-751 85 Uppsala, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Automatic Data Processing / methods*
Carcinoma, Squamous Cell / drug therapy,  genetics,  metabolism*
Caspases / metabolism
Combinatorial Chemistry Techniques / methods
Drug Evaluation, Preclinical / methods
Gene Expression Profiling / methods*
Hela Cells
Humans
Models, Biological
Oligonucleotide Array Sequence Analysis
Phenotype
Phosphodiesterase Inhibitors / pharmacology
Phosphoric Diester Hydrolases / metabolism
Pyridazines / pharmacology
Quinazolines
RNA, Messenger / metabolism
Signal Transduction / genetics*
Chemical
Reg. No./Substance:
0/Phosphodiesterase Inhibitors; 0/Pyridazines; 0/Quinazolines; 0/RNA, Messenger; 101975-10-4/zardaverine; 70018-51-8/quazinone; 84243-58-3/imazodan; EC 3.1.4.-/Phosphoric Diester Hydrolases; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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