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Novel activity of acriflavine against colorectal cancer tumor cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
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2011 (English)In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 102, no 12, 2206-2213 p.Article in journal (Refereed) Published
Abstract [en]

A high-throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5-fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis-specific cancer drugs.

Place, publisher, year, edition, pages
2011. Vol. 102, no 12, 2206-2213 p.
Keyword [en]
Acriflavine, colorectal cancer, topoisomerase, drug screening
National Category
Pharmacology and Toxicology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-130189DOI: 10.1111/j.1349-7006.2011.02097.xISI: 000297202800013OAI: oai:DiVA.org:uu-130189DiVA: diva2:347950
Note

De två första författarna delar förstaförfattarskapet

Available from: 2010-09-03 Created: 2010-09-03 Last updated: 2017-12-12Bibliographically 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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Hassan, SaadiaLaryea, DanielMahteme, HaileFelth, JennyFryknäs, MårtenRickardson, LindaGullbo, JoachimGraf, WilhelmPålman, LarsGlimelius, BengtLarsson, RolfNygren, Peter

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Hassan, SaadiaLaryea, DanielMahteme, HaileFelth, JennyFryknäs, MårtenRickardson, LindaGullbo, JoachimGraf, WilhelmPålman, LarsGlimelius, BengtLarsson, RolfNygren, Peter
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