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Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
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2013 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 31, no 3, 587-598 p.Article in journal (Other academic) Published
Abstract [en]

Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.

Place, publisher, year, edition, pages
2013. Vol. 31, no 3, 587-598 p.
Keyword [en]
gambogic acid, cancer, cytotoxic, proteasome inhibition
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Pharmacognosy; Clinical Pharmacology
URN: urn:nbn:se:uu:diva-147799DOI: 10.1007/s10637-012-9902-yISI: 000318657000010OAI: oai:DiVA.org:uu-147799DiVA: diva2:401296
Available from: 2011-03-02 Created: 2011-02-28 Last updated: 2013-06-17Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 141
cytotoxic, cardiac glycoside, gambogic acid, cancer, mechanism of action
National Category
Pharmaceutical Sciences
Research subject
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)
Available from: 2011-03-25 Created: 2011-03-02 Last updated: 2011-05-04Bibliographically approved

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Felth, JennyHaglund, CarolineGullbo, JoachimLarsson, RolfBohlin, LarsFryknäs, MårtenRickardson, Linda
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