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      Betulin Is a Potent Anti-Tumor Agent that Is Enhanced by Cholesterol

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          Abstract

          Betulinic Acid (BetA) and its derivatives have been extensively studied in the past for their anti-tumor effects, but relatively little is known about its precursor Betulin (BE). We found that BE induces apoptosis utilizing a similar mechanism as BetA and is prevented by cyclosporin A (CsA). BE induces cell death more rapidly as compared to BetA, but to achieve similar amounts of cell death a considerably higher concentration of BE is needed. Interestingly, we observed that cholesterol sensitized cells to BE-induced apoptosis, while there was no effect of cholesterol when combined with BetA. Despite the significantly enhanced cytotoxicity, the mode of cell death was not changed as CsA completely abrogated cell death. These results indicate that BE has potent anti-tumor activity especially in combination with cholesterol.

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          Pharmacological properties of the ubiquitous natural product betulin.

          Sami Alakurtti, S Koskimies, Jari Yli-Kauhaluoma … (2006)
          Betulin (lup-20(29)-ene-3beta,28-diol) is an abundant naturally occurring triterpene and it is found predominantly in bushes and trees forming the principal extractive (up to 30% of dry weight) of the bark of birch trees. Presently, there is no significant use for this easily isolable compound, which makes it a potentially important raw material for polymers and a precursor of biologically active compounds. Betulin can be easily converted to betulinic acid, which possesses a wide spectrum of biological and pharmacological activities. Betulinic acid has antimalarial and anti-inflammatory activities. Betulinic acid and its derivatives have especially shown anti-HIV activity and cytotoxicity against a variety of tumor cell lines comparable to some clinically used drugs. A new mechanism of action has been confirmed for some of the most promising anti-HIV derivatives, which makes them potentially useful additives to the current anti-HIV therapy. Betulinic acid is specifically cytotoxic to several tumor cell lines by inducing apoptosis in cells. Moreover, it is non-toxic up to 500 mg/kg body weight in mice. The literature concerning derivatization of betulin for structure-activity relationship (SAR) studies and its pharmacological properties is reviewed.
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            Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection.

            Robert H. Cichewicz, Samir Kouzi (2003)
            3beta-Hydroxy-lup-20(29)-en-28-oic acid (betulinic acid) is a pentacyclic lupane-type triterpene that is widely distributed throughout the plant kingdom. A variety of biological activities have been ascribed to betulinic acid including anti-inflammatory and in vitro antimalarial effects. However, betulinic acid is most highly regarded for its anti-HIV-1 activity and specific cytotoxicity against a variety of tumor cell lines. Interest in developing even more potent anti-HIV agents based on betulinic acid has led to the discovery of a host of highly active derivatives exhibiting greater potencies and better therapeutic indices than some current clinical anti-HIV agents. While its mechanism of action has not been fully determined, it has been shown that some betulinic acid analogs disrupt viral fusion to the cell in a post-binding step through interaction with the viral glycoprotein gp41 whereas others disrupt assembly and budding of the HIV-1 virus. With regard to its anticancer properties, betulinic acid was previously reported to exhibit selective cytotoxicity against several melanoma-derived cell lines. However, more recent work has demonstrated that betulinic acid is cytotoxic against other non-melanoma (neuroectodermal and malignant brain tumor) human tumor varieties. Betulinic acid appears to function by means of inducing apoptosis in cells irrespective of their p53 status. Because of its selective cytotoxicity against tumor cells and favorable therapeutic index, even at doses up to 500 mg/kg body weight, betulinic acid is a very promising new chemotherapeutic agent for the treatment of HIV infection and cancer. Copyright 2003 Wiley Periodicals, Inc.
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              What's so special about cholesterol?

              Ole G. Mouritsen, Martin Zuckermann (2004)
              Cholesterol (or other higher sterols such as ergosterol and phytosterols) is universally present in large amounts (20-40 mol%) in eukaryotic plasma membranes, whereas it is universally absent in the membranes of prokaryotes. Cholesterol has a unique ability to increase lipid order in fluid membranes while maintaining fluidity and diffusion rates. Cholesterol imparts low permeability barriers to lipid membranes and provides for large mechanical coherence. A short topical review is given of these special properties of cholesterol in relation to the structure of membranes, with results drawn from a variety of theoretical and experimental studies. Particular focus is put on cholesterol's ability to promote a special membrane phase, the liquid-ordered phase, which is unique for cholesterol (and other higher sterols like ergosterol) and absent in membranes containing the cholesterol precursor lanosterol. Cholesterol's role in the formation of special membrane domains and so-called rafts is discussed.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2009
                Publication date (Electronic): 28 April 2009
                Volume: 4
                Issue: 4
                Electronic Location Identifier: e1
                Affiliations
                [1 ]Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands
                [2 ]Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, The Netherlands
                Ordway Research Institute, United States of America
                Author notes

                Conceived and designed the experiments: FM JHK JPM. Performed the experiments: FM JPM. Analyzed the data: FM JHK JPM. Wrote the paper: FM JPM.

                Article
                Publisher ID: 09-PONE-RA-08671R1
                DOI: 10.1371/journal.pone.0005361
                PMC ID: 2671171
                PubMed ID: 19399186
                SO-VID: 5cc39724-ebbb-4efc-a14c-0d5f7ca8897e
                Copyright © Mullauer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 12 February 2009
                Date accepted : 23 March 2009
                Page count
                Pages: 8
                Categories
                Subject: Research Article
                Subject: Cell Biology
                Subject: Oncology
                Subject: Cell Biology/Cellular Death and Stress Responses
                Subject: Oncology/Oncology Agents

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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