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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Cancer Pharmacology and Informatics/Rolf Larsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
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2006 (English)In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 11, no 5, 457-468 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2006. Vol. 11, no 5, 457-468 p.
Keyword [en]
drug screening, annotated compound library, pathway analysis, microarray
National Category
Medical and Health Sciences Engineering and Technology
Identifiers
URN: urn:nbn:se:uu:diva-18015DOI: 10.1177/1087057106288048ISI: 000239999200001PubMedID: 16928983OAI: oai:DiVA.org:uu-18015DiVA: diva2:45786
Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Molecular Screening for Target Discovery in Cancer
Open this publication in new window or tab >>Molecular Screening for Target Discovery in Cancer
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer is one of the major causes of death in the western world. Resistance to anti-cancer drugs and diagnostic difficulties are major obstacles to successful treatment. This thesis describes studies based on microarray expression analysis and high-throughput compound screening for identification of resistance mechanisms, drug targets and diagnostic markers.

In paper I-IV, we applied global expression analysis and measurements of drug response in a human tumor cell line panel to identify drug targets and resistance mechanisms. In paper I, we identified gene transcript levels that correlate with drug resistance and sensitivity. Both well known and new potential markers and mechanisms were identified. In paper II, we showed that STAT1 activity is associated with cross-resistance to both doxorubicin and radiation in vitro and that fludarabine can counteract STAT1 activity and reduce resistance. In Paper III-IV, cell lines were exposed to a compound library consisting of more than thousand different substances in a high-throughput screening effort. These studies revealed that cell line models of squamous cell carcinoma (Paper III) and drug resistant myeloma (Paper IV) are sensitive to phosphodiesterase inhibitors and glucocorticoids respectively. The target molecules for these drugs were over-expressed at the mRNA level and constitute likely explanations for the observed drug potency. In paper V, we identified mRNA markers for the distinction between two types of thyroid tumors, thyroid follicular adenomas and thyroid follicular carcinomas, by means of microarray expression analysis. Our results indicated that distinction between the two tumor types is possible with a small number of markers.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 42 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 162
Keyword
Genetics, Cancer, Drug resistance, Microarray, High-throughput screening, Genetik
Identifiers
urn:nbn:se:uu:diva-7086 (URN)91-554-6620-6 (ISBN)
Public defence
2006-09-21, Rudbecksalen, C11, Rudbecklaboratoriet, Uppsala, 13:15 (English)
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Available from: 2006-09-01 Created: 2006-09-01 Last updated: 2009-05-12Bibliographically approved

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Fryknäs, MårtenRickardson, LindaWickström, MalinGullbo, JoachimNygren, PeterGustafsson, Mats G.Isaksson, AndersLarsson, Rolf

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