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Characterization of the cytotoxic activity of the indoloquinoline alkaloid cryptolepine in human tumour cell lines and primary cultures of tumour cells from patients
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, Clinical Pharmacology. (Cancer Pharmacology and Informatics)
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2009 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 27, no 5, 402-411 p.Article in journal (Refereed) Published
Abstract [en]

The plant derived indoloquinoline alkaloid cryptolepine was investigated for its cytotoxic properties in 12 human tumour cell lines and in primary cultures of tumour cells from patients. The fluorometric microculture cytotoxicity assay was used to assess cytotoxicity and DNA micro-array analysis to evaluate gene expression. Cryptolepine mean IC(50) in the cell line panel was 0.9 muM compared with 1.0 and 2.8 muM in haematological and solid tumour malignancies, respectively. Among patient solid tumour samples, those from breast cancer were the most sensitive and essentially as sensitive as haematological malignancies. Cryptolepine activity showed highest correlations to topoisomerase II and microtubule targeting drugs. In the cell lines cryptolepine activity was essentially unaffected by established mechanisms of drug resistance. A number of genes were identified as associated with cryptolepine activity. In conclusion, cryptolepine shows interesting in vitro cytotoxic properties and its further evaluation as an anti-cancer drug seems warranted.

Place, publisher, year, edition, pages
2009. Vol. 27, no 5, 402-411 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-102563DOI: 10.1007/s10637-008-9185-5ISI: 000269884100002PubMedID: 18853102OAI: oai:DiVA.org:uu-102563DiVA: diva2:216382
Available from: 2009-05-08 Created: 2009-05-08 Last updated: 2012-03-15Bibliographically approved
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)
Opponent
Supervisors
Available from: 2010-09-28 Created: 2010-09-06 Last updated: 2010-09-30Bibliographically approved

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Larsson, Rolf

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