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Modulation of pyridyl cyanoguanidine (CHS 828) induced cytotoxicity by 3-aminobenzamide in U-937 GTB cells
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
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2002 In: Biochemical Pharmacology, Vol. 63, no 8, 1491-1498 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 63, no 8, 1491-1498 p.
Identifiers
URN: urn:nbn:se:uu:diva-91475OAI: oai:DiVA.org:uu-91475DiVA: diva2:164218
Available from: 2004-03-24 Created: 2004-03-24Bibliographically approved
In thesis
1. Cellular Pharmacology of the Novel Antitumoural Cyanoguanidine CHS 828
Open this publication in new window or tab >>Cellular Pharmacology of the Novel Antitumoural Cyanoguanidine CHS 828
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The antitumoural cyanoguanidine CHS 828 has shown promising activity in a number of preclinical and clinical studies. However, the mechanisms underlying the cell death induced by CHS 828 has not been clarified. This thesis describes in vitro studies of the cellular pharmacology of CHS 828.

CHS 828 induced cell death with necrosis like features in the lymphoma cell line U-937 GTB. Addition of 3-aminobenzamide, an inhibitor of ADP-ribosylation, resulted in a decreased sensitivity to CHS 828 and a shift in the mode of cell death towards apoptosis.

Mouse fibroblasts lacking the enzyme PARP-1 were more sensitive to CHS 828 compared to normal fibroblasts. CHS 828 was able to induce p53 in normal fibroblasts but this effect does not seem to be necessary to induce cell death.

Characterization of two CHS 828 resistant cell lines indicated that they were selectively resistant to cyanoguanidines. Known mechanisms of anticancer drug resistance did not seem to account for the cyanoguanidine resistance. One possible resistance mediating protein, which was upregulated in the resistant cells, was epidermal fatty acid binding protein.

A novel high content screening assay was also developed. The assay was shown to be suitable both for screening of potential novel antitumoural substances as well for mechanistic studies. In the assay, CHS 828 induced caspase-3 activity and reduction in mitochondrial membrane potential, both signs of apoptosis, in U-937 GTB cells. However, nuclei in exposed cells did not show nuclear fragmentation, one of the hallmarks of apoptosis.

CHS 828 was also shown to indirectly inhibit the proteasome activity in U-937 GTB cells.

In conclusion, the results presented provide new insights into the metabolic and molecular events involved in cell death induced by CHS 828.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 31 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1330
Keyword
Pharmacology, CHS 828, Cyanoguanidines, Oncology, Pharmacology, Farmakologi
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-4088 (URN)91-554-5902-1 (ISBN)
Public defence
2004-04-15, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-03-24 Created: 2004-03-24Bibliographically approved

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