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Ex Vivo Activity of Cardiac Glycosides in Acute Leukaemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Hematologi)
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 Medicine, Department of Medical Sciences, Clinical Pharmacology. (Cancer Pharmacology and Informatics/Rolf Larsson)
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, e15718- p.Article in journal (Refereed) Published
Abstract [en]

Background:

Despite years of interest in the anti-cancerous effects of cardiac glycosides (CGs), and numerous studies in vitro and in animals, it has not yet been possible to utilize this potential clinically. Reports have demonstrated promising in vitro effects on different targets as well as a possible therapeutic index/selectivity in vitro and in experimental animals. Recently, however, general inhibition of protein synthesis was suggested as the main mechanism of the anti-cancerous effects of CGs. In addition, evidence of species differences of a magnitude sufficient to explain the results of many studies called for reconsideration of earlier results.

Principal Findings:

In this report we identified primary B-precursor and T-ALL cells as being particularly susceptible to the cytotoxic effects of CGs. Digitoxin appeared most potent and IC50 values for several patient samples were at concentrations that may be achieved in the clinic. Significant protein synthesis inhibition at concentrations corresponding to IC50 was demonstrated in colorectal tumour cell lines moderately resistant to the cytotoxic effects of digoxin and digitoxin, but not in highly sensitive leukaemia cell lines.

Conclusion:

It is suggested that further investigation regarding CGs may be focused on diagnoses like T-and B-precursor ALL.

Place, publisher, year, edition, pages
2011. Vol. 6, no 1, e15718- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-147765DOI: 10.1371/journal.pone.0015718ISI: 000286511200012PubMedID: 21246039OAI: oai:DiVA.org:uu-147765DiVA: diva2:401007
Available from: 2011-03-01 Created: 2011-02-28 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Studies of Cytotoxic Compounds of Natural Origin and their Mechanisms of Action
Open this publication in new window or tab >>Studies of Cytotoxic Compounds of Natural Origin and their Mechanisms of Action
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer incidence is increasing and novel anticancer drugs with new mechanisms of action are essential for future chemotherapeutic treatment. Natural products have historically played an important role in the development of anti-cancer drugs and have potential to do so also in the future. In this thesis two classes of natural products are identified as possible drug lead candidates, and the mechanisms of their action are elucidated.

Initially, in a screening of a compound library for cytotoxic effects in colon cancer cells, natural products with potent activity were identified. Based on their potency, and on previously reported activities in cancer cells, two main groups of compounds, cardiac glycosides (CGs) and gambogic acid (GA) analogues, were selected for further in-depth studies.

The concentration-dependent cytotoxicity was confirmed in cell lines of different origin. Cardiac glycosides were mainly evaluated for their activity in colon cancer cells and in leukemic cells, whereas the GA analogues were studied using a resistance-based panel of ten human cancer cell lines. Using activity profiles and the ChemGPS-NP model, the compounds were compared, structurally and mechanistically, to standard chemotherapeutic drugs. The results from these analyses suggested that the CGs and the GA analogues act by mechanisms different from those of antimetabolites, alkylating agents, topoisomerase I and II inhibitors, or tubulin-active agents. By analysis of drug-induced gene expression, one GA analogue, dihydro GA, was identified as a possible inhibitor of the ubiquitin-proteasome system (UPS), and the CGs showed similarities to protein synthesis inhibitors.

Starting from these hypotheses, we further investigated the mechanisms of actions on a molecular level. The results showed that GA and dihydro GA act as inhibitors of the 20S proteasome chymotrypsin activity, leading to accumulation of ubiquitinated proteins. The CGs were confirmed to inhibit protein synthesis in colon cancer cell lines. However, interestingly, in leukemia cell lines, it seemed that the CGs act through a different, yet unexplored, mechanism of action. The leukemic cells (pre-B and T-ALL) were particularly susceptible to the cytotoxic effects of CGs, including at concentrations that may be achievable in the clinic.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 56 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 141
Keyword
cytotoxic, cardiac glycoside, gambogic acid, cancer, mechanism of action
National Category
Pharmaceutical Sciences
Research subject
Pharmacognosy
Identifiers
urn:nbn:se:uu:diva-148114 (URN)978-91-554-8023-3 (ISBN)
Public defence
2011-04-15, B21, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Available from: 2011-03-25 Created: 2011-03-02 Last updated: 2011-05-04Bibliographically approved

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Fryknäs, MårtenLarsson, Rolf

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