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      Anticancer and Immunogenic Properties of Cardiac Glycosides

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          Abstract

          Cardiac glycosides (CGs) are natural compounds widely used in the treatment of several cardiac conditions and more recently have been recognized as potential antitumor compounds. They are known to be ligands for Na/K-ATPase, which is a promising drug target in cancer. More recently, in addition to their antitumor effects, it has been suggested that CGs activate tumor-specific immune responses. This review summarizes the anticancer aspects of CGs as new strategies for immunotherapy and drug repositioning (new horizons for old players), and the possible new targets for CGs in cancer cells.

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          Novel therapeutic applications of cardiac glycosides.

          Ioannis Prassas, Eleftherios P. Diamandis (2008)
          Cardiac glycosides are a diverse family of naturally derived compounds that bind to and inhibit Na+/K+-ATPase. Members of this family have been in clinical use for many years for the treatment of heart failure and atrial arrhythmia, and the mechanism of their positive inotropic effect is well characterized. Exciting recent findings have suggested additional signalling modes of action of Na+/K+-ATPase, implicating cardiac glycosides in the regulation of several important cellular processes and highlighting potential new therapeutic roles for these compounds in various diseases. Perhaps most notably, the increased susceptibility of cancer cells to these compounds supports their potential use as cancer therapies, and the first generation of glycoside-based anticancer drugs are currently in clinical trials.
          Article 0 comments Cited 190 times – based on 0 reviews     Review now
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            Cardiac glycosides exert anticancer effects by inducing immunogenic cell death.

            Abdul Qader Sukkurwala, Guido Kroemer, Erika Vacchelli … (2012)
            Some successful chemotherapeutics, notably anthracyclines and oxaliplatin, induce a type of cell stress and death that is immunogenic, hence converting the patient's dying cancer cells into a vaccine that stimulates antitumor immune responses. By means of a fluorescence microscopy platform that allows for the automated detection of the biochemical hallmarks of such a peculiar cell death modality, we identified cardiac glycosides (CGs) as exceptionally efficient inducers of immunogenic cell death, an effect that was associated with the inhibition of the plasma membrane Na(+)- and K(+)-dependent adenosine triphosphatase (Na(+)/K(+)-ATPase). CGs exacerbated the antineoplastic effects of DNA-damaging agents in immunocompetent but not immunodeficient mice. Moreover, cancer cells succumbing to a combination of chemotherapy plus CGs could vaccinate syngeneic mice against a subsequent challenge with living cells of the same type. Finally, retrospective clinical analyses revealed that the administration of the CG digoxin during chemotherapy had a positive impact on overall survival in cohorts of breast, colorectal, head and neck, and hepatocellular carcinoma patients, especially when they were treated with agents other than anthracyclines and oxaliplatin.
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              Cardiac glycosides as novel cancer therapeutic agents.

              Peiying Yang, P. Newman, K Block … (2008)
              The class of steroid-like compounds designated cardiac glycosides includes well-known drugs such as digoxin, digitoxin, and ouabain. Their continued efficacy in treatment of congestive heart failure and as anti-arrhythmic agents is well appreciated. Less well known, however, is the emerging role of this category of compounds in the prevention and/or treatment of proliferative diseases such as cancer. New findings within the past five years have revealed these compounds to be involved in complex cell-signal transduction mechanisms, resulting in selective control of human tumor but not normal cellular proliferation. As such, they represent a promising form of targeted cancer chemotherapy. New clinical studies of their anticancer potential as single or adjuvant treatments may provide insight into these potentially valuable therapeutic options. This review focuses on recent findings on cellular pharmacology of cardiac glycosides as they relate to treatment of human cancer and attempts to explain why these agents have been overlooked in the past.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 08 November 2017
                Publication date Collection: November 2017
                Volume: 22
                Issue: 11
                Electronic Location Identifier: 1932
                Affiliations
                [1 ]Programa de Pós-Graduação em Farmácia, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis SC 88040-900, Brazil; nairafzs@ 123456gmail.com (N.F.Z.S.); claudia.simoes@ 123456ufsc.br (C.M.O.S.)
                [2 ]Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Hôpital Kirchberg, 9, rue Edward Steichen, 2540 Luxembourg, Luxembourg; claudia.cerella@ 123456lbmcc.lu
                [3 ]Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Building 29 Room 223, 1 Gwanak-ro, Gwanak-gu 08826, Korea
                Author notes
                [* ]Correspondence: marcdiederich@ 123456snu.ac.kr ; Tel.: +82-2-880-8919
                Author information
                https://orcid.org/0000-0003-0115-4725
                Article
                Publisher ID: molecules-22-01932
                DOI: 10.3390/molecules22111932
                PMC ID: 6150164
                PubMed ID: 29117117
                SO-VID: b7ce6738-de99-4d28-a343-bf40bd712171
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 05 October 2017
                Date accepted : 04 November 2017
                Categories
                Subject: Review

                Keywords: cardiac glycosides,anticancer,immunogenic cell death,cytotoxic effects,cancer cells,na/k-atpase
                Data availability:
                Keywords: cardiac glycosides, anticancer, immunogenic cell death, cytotoxic effects, cancer cells, na/k-atpase

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