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

被引:19
作者
Fryknas, Marten
Rickardson, Linda
Wickstrom, Malin
Dhar, Sumeer
Lovborg, Henrik
Gullbo, Joachim
Nygren, Peter
Gustafsson, Mats G.
Isaksson, Anders
Larsson, Rolf [1 ]
机构
[1] Univ Uppsala, Dept Med Sci, Div Clin Pharmacol, S-75185 Uppsala, Sweden
[2] Univ Uppsala, Dept Genet & Pathol, S-75185 Uppsala, Sweden
[3] Univ Uppsala, Dept Oncol Radiol & Clin Immunol, S-75185 Uppsala, Sweden
[4] Univ Uppsala, Dept Engn Sci, S-75185 Uppsala, Sweden
关键词
drug screening; annotated compound library; pathway analysis; microarray;
D O I
10.1177/1087057106288048
中图分类号
Q5 [生物化学];
学科分类号
071010 [生物化学与分子生物学]; 081704 [应用化学];
摘要
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.
引用
收藏
页码:457 / 468
页数:12
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