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Selective cytotoxicity evaluation in anticancer drug screening of fractionated plant extracts
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
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2002 (English)In: Journal of Biomolecular Screening, ISSN 1087-0571, E-ISSN 1552-454X, Vol. 7, no 4, 333-340 p.Article in journal (Refereed) Published
Abstract [en]

Chosen to reflect biodiversity in a phylogenetic sense, 100 fractionated plant extracts were screened in vitro for cytotoxicity following extraction and fractionation (polypeptide isolation). Of these 100 extracts, 30 were selected and then characterized preliminarily for antitumor potency and mode of action by testing them on two cell lines and primary cultures of human tumor cells. On the basis of cytotoxicity potency, 10 of the extracts were further characterized for anticancer activity in 10 human tumor cell lines. This final testing resulted in seven potential lead plants with superior evidence of antitumor potential: Colchicum autumnale L. (Colchicaceae), Digitalis lanata Ehrh. and Digitalis purpurea L. (Plantaginaceae), Helleborus cyclophyllus Boiss. (Ranunculaceae), Menyanthes trifoliata L. (Menyanthaceae), and Viola arvensis Murr. and Viola patrinii Ging. (Violaceae). Within a database of antitumor compounds, the activity profiles of the extracts from these seven plants were compared, by correlation analysis, with those of more than 100 other compounds, including 39 standard drugs from different classes of cytotoxic mechanisms. The activity profiles of six of these candidates were uncorrelated with those of the standard drugs, possibly indicating new pathways of drug-mediated cell death.

Place, publisher, year, edition, pages
2002. Vol. 7, no 4, 333-340 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-92803DOI: 10.1177/108705710200700405PubMedID: 12230887OAI: oai:DiVA.org:uu-92803DiVA: diva2:166101
Available from: 2005-04-01 Created: 2005-04-01 Last updated: 2012-03-06Bibliographically approved
In thesis
1. Cytotoxic Compounds of Plant Origin – Biological and Chemical Diversity
Open this publication in new window or tab >>Cytotoxic Compounds of Plant Origin – Biological and Chemical Diversity
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Cytotoxiska föreningar från växter – biologisk och kemisk diversitet
Abstract [en]

The development of resistance by tumour cells to chemotherapeutic agents is a major problem in cancer treatments. One way to counter this is to find compounds with cytotoxic mechanisms other than those of drugs in clinical use today. The biological and chemical diversity encountered in Nature provide opportunities to discover completely new chemical classes of compounds. Some of these may represent previously unknown anticancer agents, and in some cases, novel, potentially relevant cytotoxic mechanisms.

The selection of plants for the cytotoxic investigation in this project was designed to cover large parts of the angiosperm system, providing a broad representation of species. Extracts of the plants were subjected to a polypeptide fractionation protocol, followed by bioassay-guided isolation, yielding series of fractions with increasing purity and cytotoxicity. The cytotoxicity assay included tumour cells from patients and a cell-line panel including ten different cell lines representing several types of resistant and non-resistant tumours. This screening strategy allowed fractions and compounds acting with novel mechanisms to be detected at an early stage.

The compounds isolated represent substantial chemical diversity and originate from diverse parts of the phylogenetic spectrum examined. They include the highly potent cytotoxic alkaloid, thiobinupharidine, the structure of which was determined by NMR techniques. Furthermore, two types of compound were shown to have previously unreported cytoxic activity: cyclotides (small macrocyclic polypeptides, in this case from violets) and polypeptides, possibly of thionine type, of loranthaceaeous mistletoes (collected in Panama). The well known cardiac glycosides from the foxglove, Digitalis, were identified as being responsible for the anti-tumour activity of this species.

In conclusion, the results obtained in this project show that selection based on phylogenetic information, together with a robust and reliable method to detect cytotoxicity, can be a useful approach for exploring the plant kingdom for cytotoxic substances.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 71 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 7
Pharmacognosy, pharmacognosy, cytotoxicity, antitumour, Nuphar alkaloid, cyclotide, thionin, cardiac glycoside, Farmakognosi
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-5728 (URN)91-554-6197-2 (ISBN)
Public defence
2005-04-22, Room C8:301, BMC, Husargatan 1, Uppsala, 09:15
Available from: 2005-04-01 Created: 2005-04-01Bibliographically approved

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