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Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi. (Cancer Pharmacology and Informatics/Rolf Larsson)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi. (Cancer Pharmacology and Informatics/Rolf Larsson)
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2009 (Engelska)Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 72, nr 11, s. 1969-1974Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Cardiac glycosides have been reported to exhibit cytotoxic activity against several different cancer types, but studies against colorectal cancer are lacking. In a screening procedure aimed at identifying natural products with activity against colon cancer, several cardiac glycosides were shown to be of interest, and five of these were further evaluated in different colorectal cancer cell lines and primary cells from patients. Convallatoxin (1), oleandrin (4), and proscillaridin A (5) were identified as the most potent compounds (submicromolar IC50 values), and digitoxin (2) and digoxin (3), which are used in cardiac disease, exhibited somewhat lower activity (IC50 values 0.27−4.1 μM). Selected cardiac glycosides were tested in combination with four clinically relevant cytotoxic drugs (5-fluorouracil, oxaliplatin, cisplatin, irinotecan). The combination of 2 and oxaliplatin exhibited synergism including the otherwise highly drug-resistant HT29 cell line. A ChemGPS-NP application comparing modes of action of anticancer drugs identified cardiac glycosides as a separate cluster. These findings demonstrate that such substances may exhibit significant activity against colorectal cancer cell lines, by mechanisms disparate from currently used anticancer drugs, but at concentrations generally considered not achievable in patient plasma.

Ort, förlag, år, upplaga, sidor
2009. Vol. 72, nr 11, s. 1969-1974
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Farmakognosi
Identifikatorer
URN: urn:nbn:se:uu:diva-125009DOI: 10.1021/np900210mISI: 000272227600010PubMedID: 19894733OAI: oai:DiVA.org:uu-125009DiVA, id: diva2:318249
Tillgänglig från: 2010-05-07 Skapad: 2010-05-07 Senast uppdaterad: 2018-01-12
Ingår i avhandling
1. Studies of Cytotoxic Compounds of Natural Origin and their Mechanisms of Action
Öppna denna publikation i ny flik eller fönster >>Studies of Cytotoxic Compounds of Natural Origin and their Mechanisms of Action
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2011. s. 56
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 141
Nyckelord
cytotoxic, cardiac glycoside, gambogic acid, cancer, mechanism of action
Nationell ämneskategori
Farmaceutiska vetenskaper
Forskningsämne
Farmakognosi
Identifikatorer
urn:nbn:se:uu:diva-148114 (URN)978-91-554-8023-3 (ISBN)
Disputation
2011-04-15, B21, BMC, Husargatan 3, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-03-25 Skapad: 2011-03-02 Senast uppdaterad: 2018-01-12Bibliografiskt granskad

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