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Cellular Pharmacology of the Novel Antitumoural Cyanoguanidine CHS 828
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
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. , p. 31
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1330
Keywords [en]
Pharmacology, CHS 828, Cyanoguanidines, Oncology, Pharmacology
Keywords [sv]
Farmakologi
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-4088ISBN: 91-554-5902-1 (print)OAI: oai:DiVA.org:uu-4088DiVA, id: diva2:164222
Public defence
2004-04-15, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 09:15
Opponent
Supervisors
Available from: 2004-03-24 Created: 2004-03-24 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Modulation of pyridyl cyanoguanidine (CHS 828) induced cytotoxicity by 3-aminobenzamide in U-937 GTB cells
Open this publication in new window or tab >>Modulation of pyridyl cyanoguanidine (CHS 828) induced cytotoxicity by 3-aminobenzamide in U-937 GTB cells
Show others...
2002 In: Biochemical Pharmacology, Vol. 63, no 8, p. 1491-1498Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91475 (URN)
Available from: 2004-03-24 Created: 2004-03-24Bibliographically approved
2. Action of a novel anticancer agent, CHS 828, on mouse fibriblasts: Increased sensitivity of cells lacking poly (ADP-ribose) polymerase-1
Open this publication in new window or tab >>Action of a novel anticancer agent, CHS 828, on mouse fibriblasts: Increased sensitivity of cells lacking poly (ADP-ribose) polymerase-1
2002 In: Cancer Research, ISSN 0008-5472, Vol. 62, p. 4206-4211Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91476 (URN)
Available from: 2004-03-24 Created: 2004-03-24Bibliographically approved
3. Development and characterization of two human tumor sublines expressing high-grade resistance to the cyanoguanidine CHS 828
Open this publication in new window or tab >>Development and characterization of two human tumor sublines expressing high-grade resistance to the cyanoguanidine CHS 828
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2004 In: Anti-Cancer Drugs, Vol. 15, no 1, p. 45-54Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91477 (URN)
Available from: 2004-03-24 Created: 2004-03-24Bibliographically approved
4. Multiparametric evaluation of apoptosis: effects of standard cytotoxic agents and the cyanoguanidine CHS 828
Open this publication in new window or tab >>Multiparametric evaluation of apoptosis: effects of standard cytotoxic agents and the cyanoguanidine CHS 828
2004 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 3, no 5, p. 521-526Article in journal (Refereed) Published
Abstract [en]

A multiparametric high-content screening assay for measurement of apoptosis was developed. HeLa cells and lymphoma U-937 cells were exposed to cytotoxic drugs in flat-bottomed optical microtiter plates. After incubation, the DNA-binding dye Hoechst 33342, fluorescein-tagged probes that covalently bind active caspases and chloromethyl-X-rosamine to detect mitochondrial membrane potential (MMP) were added. Image acquisition and quantitative measurement of fluorescence in a defined number of cells per well was performed using the automated image capture and analysis instrument ArrayScan. The usefulness of the assay was tested in cells exposed to standard cytotoxic drugs as well as in experimental cytotoxic cyanoguanidine CHS 828. A time- and dose-dependent activation of caspase-3, decrease in MMP, and increase in nuclear fragmentation and condensation were observed for the standard drugs, with the ability to correlate the parameters on a single cell basis. CHS 828 induced caspase-3 activation and reduction in MMP with modest changes in nuclear morphology. The method described was considered to be a rapid and information-rich apoptosis assay suitable both for correlating morphological and biochemical apoptotic events in single cells as well as for screening and evaluation of novel substances with apoptosis-inducing capabilities.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91478 (URN)15141009 (PubMedID)
Available from: 2004-03-24 Created: 2004-03-24 Last updated: 2017-12-14Bibliographically approved

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