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Inhibition of proteasome activity, nuclear factor-κB translocation and cell survival by the antialcoholism drug disulfiram
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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2006 In: International Journal of Cancer, Vol. 118, 1577-1580 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 118, 1577-1580 p.
URN: urn:nbn:se:uu:diva-96719OAI: oai:DiVA.org:uu-96719DiVA: diva2:171388
Available from: 2008-02-15 Created: 2008-02-15Bibliographically approved
In thesis
1. New Methods to Screen for Cancer Drugs and to Evaluate their Mechanism of Action
Open this publication in new window or tab >>New Methods to Screen for Cancer Drugs and to Evaluate their Mechanism of Action
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer is a common disease and due to problems with resistance against cancer drugs and the limited benefit from chemotherapy in many diagnoses, there is a need to develop new cancer drugs. In this thesis new methods to screen for cancer drugs and to evaluate their mechanism of action are discussed.

In Paper I, it was found that by studying the gene expression of a cell line panel and combining the data with sensitivity data of a number of cytotoxic drugs, it was possible to cluster compounds according to mechanism of action as well as identifying genes associated with chemosensitivity.

In Paper II, studies of compounds with selective activity in drug-resistant cell lines revealed the glucocorticoids as a group of interesting compounds. The glucocorticoid receptor was overexpressed in 8226/Dox40 and the difference in sensitivity was abolished when the cells were treated with a glucocorticoid receptor antagonist.

In Paper III, an image-based screening method for new proteasome inhibitors was successfully developed and the compounds disulfiram, PDTC and NSC 95397 were identified as inhibitors of the proteasome.

In Paper IV, disulfiram and PDTC were shown to induce cytotoxic activity, to inhibit the activation of the transcription factor NFkappaB and to inhibit the degradation of proteins normally degraded by the proteasome.

In Paper V, NSC 95397 was shown to be cytotoxic to all cells in the resistance-based cell line panel as well as to patient samples from a variety of cancer diagnoses. Connectivity Map was successfully used as a tool to propose a new mechanism of action of NSC 95397. The gene expression induced by NSC 95397-treatment was similar to that induced by several proteasome inhibitors not present in the Connectivity Map.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 48 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 311
Pharmacology, Cancer drugs, Screening, Gene expression, Farmakologi
urn:nbn:se:uu:diva-8440 (URN)978-91-554-7086-9 (ISBN)
Public defence
2008-03-07, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15
Available from: 2008-02-15 Created: 2008-02-15 Last updated: 2011-06-17Bibliographically approved

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