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Characterization of the cytotoxic properties of the benzimidazole fungicides, benomyl and carbendazim, in human tumour cell lines and primary cultures of patient tumour cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer pharmacology and informatics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer pharmacology and informatics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer pharmacology and informatics)
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2010 (English)In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 21, no 1, 33-42 p.Article in journal (Refereed) Published
Abstract [en]

The benzimidazoles, benomyl and carbendazim, are fungicides suggested to target microtubules. Benomyl is metabolized to carbendazim, which has already been explored as an anticancer drug in phase 1 clinical trials. We further characterized the cytotoxic properties of benomyl and carbendazim in 12 human cell lines and in primary cultures of patient tumour cells with the overall aims of elucidating mechanisms of action and anticancer activity spectrum. Cytotoxicity was assessed in the short-term fluorometric microculture cytotoxicity assay and was correlated with the activity of other anticancer drugs and gene expression assessed by cDNA microarray analysis. Benomyl was generally more potent than its metabolite, carbendazim. Both showed high drug activity correlations with several established and experimental anticancer drugs, but modest association with established mechanisms of drug resistance. Furthermore, these benzimidazoles showed high correlations with genes considered relevant for the activity of several mechanistically different standard and experimental anticancer drugs, indicating multiple and broad mechanisms of action. In patient tumour samples, benomyl tended to be more active in haematological compared with solid tumour malignancies, whereas the opposite was observed for carbendazim. In conclusion, benomyl and carbendazim show interesting and diverse cytotoxic mechanisms of action and seem suitable as lead compounds for the development of new anticancer drugs.

Place, publisher, year, edition, pages
2010. Vol. 21, no 1, 33-42 p.
Keyword [en]
benomyl, carbendazim, cross-resistance, cytotoxic drug, gene expression, tumour cell
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-125014DOI: 10.1097/CAD.0b013e328330e74eISI: 000273021800004PubMedID: 19786863OAI: oai:DiVA.org:uu-125014DiVA: diva2:318278
Available from: 2010-05-07 Created: 2010-05-07 Last updated: 2017-12-12
In thesis
1. Preclinical Characterization in vivo and in vitro of Novel Agents for Cancer Chemotherapy: Studies on Benomyl, Carbendazim, Cryptolepine and Acriflavine
Open this publication in new window or tab >>Preclinical Characterization in vivo and in vitro of Novel Agents for Cancer Chemotherapy: Studies on Benomyl, Carbendazim, Cryptolepine and Acriflavine
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Preclinical methods for the identification and characterization of molecules for development into new cancer drugs were investigated. Based on repurposing, i.e. the exploration of currently prescribed drugs for new indications, and as a result of a new high throughput screening (HTS) approach, the benzimidazoles benomyl and carbendazim, the alkaloid cryptolepine and the acridine acriflavine were found interesting to characterize using these methods.

In mice the benzimidazoles inhibited 3H-thymidine incorporation in tissues with high cell renewal, with benomyl being more active than carbendazim.  They were rapidly absorbed with highest amounts seen in the liver, kidneys and gastro-intestinal lumen as evidenced from distribution of 14C-labeled drugs. In human tumour cell lines, the benzimidazoles showed a similar activity pattern but benomyl was more potent. This was true also in tumour cells from patients but carbendazim was relatively more active against solid tumours. Analyses of drug activity cross-resistance patterns and of drug activity – gene expression correlations in a cell line panel suggested multiple mechanisms of action for the benzimidazoles.

Cryptolepine was widely distributed to tissues in vivo in the mice. It was more potent than the benzimidazoles in tumour cells, with highest activity in haematological malignancies but some patient samples of breast, colon and non small-cell lung cancer were sensitive. Cross-resistance analysis indicated cryptolepine to be a topoisomerase II inhibitor whereas drug activity – gene expression correlations suggested additional mechanisms of action.

HTS on 2 000 molecules in colon cancer cell lines and normal cells identified acriflavine as a hit molecule, subsequently shown to have unprecedented activity against colorectal cancer tumour cells in patient tumour samples. Connectivity map analysis, based on drug induced gene expression perturbation patterns in a tumour cell line, indicated acriflavine to be a topoisomerase inhibitor, subsequently confirmed in a plasmid relaxation assay. In conclusion, repurposing of drugs and HTS using stringent activity criteria followed by preclinical characterization might contribute to more efficient development of new cancer drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 593
Keyword
Benzimidazoles, cryptolepine, acriflavine, cancer, high throughput screening, cytotoxic drug, gene expression
Identifiers
urn:nbn:se:uu:diva-130330 (URN)978-91-554-7882-7 (ISBN)
Public defence
2010-10-15, Enghoffsalen, Entrance 50, Ground Floor, Uppsala University Hospital, Uppsala, 13:15 (English)
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Available from: 2010-09-28 Created: 2010-09-06 Last updated: 2010-09-30Bibliographically approved

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Isaksson, AndersLarsson, RolfNygren, Peter

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