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Special Issue "Cardiotonic Steroids"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 February 2017)

Special Issue Editor

Guest Editor
Prof. Dr. Robert Kiss

Laboratorie de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Brussels, Belgium
Website | E-Mail
Interests: cancer research; natural compounds; non-apoptotic cell death; metastatis; in vivo models; multidrug resistance; glioblastoma; melanoma; cell migration; phenotypic screening

Special Issue Information

Dear Colleagues,

The sodium/potassium pump (the Na+/K+-ATPase, i.e., NaK), with its highly specific ligands (i.e., cardiotonic steroids including cardenolides and bufadienolides), seems a promising target for combating cancers associated with dismal prognoses, which mainly relate to the resistance of cancer cells (as metastatic ones) to pro-apoptotic cytotoxic insults and to the acquisition of the multidrug resistant (MDR) phenotype during chronic treatment. Indeed, NaK plays a key role in cell adhesion and has abnormal expression and activity that could be implicated in the development and progression of different cancers, including glioblastoma, melanoma, and non-small-cell lung cancers, among others. The activation of NaK triggers distinct signaling pathways in normal versus cancer cells, and several cardiotonic steroids have already been demonstrated to be less toxic in normal than in cancer cells. In addition, several cardiotonic steroids also kill various types of apoptosis-resistant and/or MDR cancer models. However, various challenges still exist to move cardiotonic steroids in clinical development for combating various types of cancers. One of these challenges relates to how managing the toxicity of these compounds, according to the limitations of existing preclinical models, will adequately predict the cardiotoxic potential of new molecules in man. Two other challenges relate to the potential of chemical modifications to reduce the cardiovascular side-effects and improve the anti-cancer activity of new molecules, and the development of tumor-targeting vectors to accumulate these compounds on tumor sites, while decreasing systemic toxicity

Prof. Dr. Robert Kiss
Guest Editor

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Keywords

  • cardiotonic steroids
  • cancer
  • drug targeting
  • medicinal chemistry
  • toxicity

Published Papers (6 papers)

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Review

Open AccessReview Anticancer and Immunogenic Properties of Cardiac Glycosides
Molecules 2017, 22(11), 1932; doi:10.3390/molecules22111932
Received: 5 October 2017 / Revised: 29 October 2017 / Accepted: 4 November 2017 / Published: 8 November 2017
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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,
[...] Read more.
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. Full article
(This article belongs to the Special Issue Cardiotonic Steroids)
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Open AccessFeature PaperReview Protein Interaction and Na/K-ATPase-Mediated Signal Transduction
Molecules 2017, 22(6), 990; doi:10.3390/molecules22060990
Received: 7 April 2017 / Revised: 1 June 2017 / Accepted: 2 June 2017 / Published: 14 June 2017
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Abstract
The Na/K-ATPase (NKA), or Na pump, is a member of the P-type ATPase superfamily. In addition to pumping ions across cell membrane, it is engaged in assembly of multiple protein complexes in the plasma membrane. This assembly allows NKA to perform many non-pumping
[...] Read more.
The Na/K-ATPase (NKA), or Na pump, is a member of the P-type ATPase superfamily. In addition to pumping ions across cell membrane, it is engaged in assembly of multiple protein complexes in the plasma membrane. This assembly allows NKA to perform many non-pumping functions including signal transduction that are important for animal physiology and disease progression. This article will focus on the role of protein interaction in NKA-mediated signal transduction, and its potential utility as target for developing new therapeutics. Full article
(This article belongs to the Special Issue Cardiotonic Steroids)
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Open AccessReview On the Many Actions of Ouabain: Pro-Cystogenic Effects in Autosomal Dominant Polycystic Kidney Disease
Molecules 2017, 22(5), 729; doi:10.3390/molecules22050729
Received: 15 March 2017 / Revised: 19 April 2017 / Accepted: 30 April 2017 / Published: 3 May 2017
Cited by 1 | PDF Full-text (1133 KB) | HTML Full-text | XML Full-text
Abstract
Ouabain and other cardenolides are steroidal compounds originally discovered in plants. Cardenolides were first used as poisons, but after finding their beneficial cardiotonic effects, they were rapidly included in the medical pharmacopeia. The use of cardenolides to treat congestive heart failure remained empirical
[...] Read more.
Ouabain and other cardenolides are steroidal compounds originally discovered in plants. Cardenolides were first used as poisons, but after finding their beneficial cardiotonic effects, they were rapidly included in the medical pharmacopeia. The use of cardenolides to treat congestive heart failure remained empirical for centuries and only relatively recently, their mechanisms of action became better understood. A breakthrough came with the discovery that ouabain and other cardenolides exist as endogenous compounds that circulate in the bloodstream of mammals. This elevated these compounds to the category of hormones and opened new lines of investigation directed to further study their biological role. Another important discovery was the finding that the effect of ouabain was mediated not only by inhibition of the activity of the Na,K-ATPase (NKA), but by the unexpected role of NKA as a receptor and a signal transducer, which activates a complex cascade of intracellular second messengers in the cell. This broadened the interest for ouabain and showed that it exerts actions that go beyond its cardiotonic effect. It is now clear that ouabain regulates multiple cell functions, including cell proliferation and hypertrophy, apoptosis, cell adhesion, cell migration, and cell metabolism in a cell and tissue type specific manner. This review article focuses on the cardenolide ouabain and discusses its various in vitro and in vivo effects, its role as an endogenous compound, its mechanisms of action, and its potential use as a therapeutic agent; placing especial emphasis on our findings of ouabain as a pro-cystogenic agent in autosomal dominant polycystic kidney disease (ADPKD). Full article
(This article belongs to the Special Issue Cardiotonic Steroids)
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Open AccessReview Na/K Pump and Beyond: Na/K-ATPase as a Modulator of Apoptosis and Autophagy
Molecules 2017, 22(4), 578; doi:10.3390/molecules22040578
Received: 21 February 2017 / Revised: 29 March 2017 / Accepted: 29 March 2017 / Published: 21 April 2017
Cited by 1 | PDF Full-text (1267 KB) | HTML Full-text | XML Full-text
Abstract
Lung cancer is a leading cause of global cancer deaths. Na/K-ATPase has been studied as a target for cancer treatment. Cardiotonic steroids (CS) trigger intracellular signalling upon binding to Na/K-ATPase. Normal lung and tumour cells frequently express different pump isoforms. Thus, Na/K-ATPase is
[...] Read more.
Lung cancer is a leading cause of global cancer deaths. Na/K-ATPase has been studied as a target for cancer treatment. Cardiotonic steroids (CS) trigger intracellular signalling upon binding to Na/K-ATPase. Normal lung and tumour cells frequently express different pump isoforms. Thus, Na/K-ATPase is a powerful target for lung cancer treatment. Drugs targeting Na/K-ATPase may induce apoptosis and autophagy in transformed cells. We argue that Na/K-ATPase has a role as a potential target in chemotherapy in lung cancer treatment. We discuss the effects of Na/K-ATPase ligands and molecular pathways inducing deleterious effects on lung cancer cells, especially those leading to apoptosis and autophagy. Full article
(This article belongs to the Special Issue Cardiotonic Steroids)
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Open AccessReview Na+i,K+i-Dependent and -Independent Signaling Triggered by Cardiotonic Steroids: Facts and Artifacts
Molecules 2017, 22(4), 635; doi:10.3390/molecules22040635
Received: 23 February 2017 / Revised: 31 March 2017 / Accepted: 11 April 2017 / Published: 14 April 2017
Cited by 1 | PDF Full-text (2910 KB) | HTML Full-text | XML Full-text
Abstract
Na+,K+-ATPase is the only known receptor of cardiotonic steroids (CTS) whose interaction with catalytic α-subunits leads to inhibition of this enzyme. As predicted, CTS affect numerous cellular functions related to the maintenance of the transmembrane gradient of monovalent cations,
[...] Read more.
Na+,K+-ATPase is the only known receptor of cardiotonic steroids (CTS) whose interaction with catalytic α-subunits leads to inhibition of this enzyme. As predicted, CTS affect numerous cellular functions related to the maintenance of the transmembrane gradient of monovalent cations, such as electrical membrane potential, cell volume, transepithelial movement of salt and osmotically-obliged water, symport of Na+ with inorganic phosphate, glucose, amino acids, nucleotides, etc. During the last two decades, it was shown that side-by-side with these canonical Na+i/K+i-dependent cellular responses, long-term exposure to CTS affects transcription, translation, tight junction, cell adhesion and exhibits tissue-specific impact on cell survival and death. It was also shown that CTS trigger diverse signaling cascades via conformational transitions of the Na+,K+-ATPase α-subunit that, in turn, results in the activation of membrane-associated non-receptor tyrosine kinase Src, phosphatidylinositol 3-kinase and the inositol 1,4,5-triphosphate receptor. These findings allowed researchers to propose that endogenous CTS might be considered as a novel class of steroid hormones. We focus our review on the analysis of the relative impact Na+i,K+i-mediated and -independent pathways in cellular responses evoked by CTS. Full article
(This article belongs to the Special Issue Cardiotonic Steroids)
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Open AccessReview The Role of Na/K-ATPase Signaling in Oxidative Stress Related to Obesity and Cardiovascular Disease
Molecules 2016, 21(9), 1172; doi:10.3390/molecules21091172
Received: 29 July 2016 / Revised: 26 August 2016 / Accepted: 1 September 2016 / Published: 3 September 2016
Cited by 4 | PDF Full-text (1028 KB) | HTML Full-text | XML Full-text
Abstract
Na/K-ATPase has been extensively studied for its ion pumping function, but, in the past several decades, has been identified as a scaffolding and signaling protein. Initially it was found that cardiotonic steroids (CTS) mediate signal transduction through the Na/K-ATPase and result in the
[...] Read more.
Na/K-ATPase has been extensively studied for its ion pumping function, but, in the past several decades, has been identified as a scaffolding and signaling protein. Initially it was found that cardiotonic steroids (CTS) mediate signal transduction through the Na/K-ATPase and result in the generation of reactive oxygen species (ROS), which are also capable of initiating the signal cascade. However, in recent years, this Na/K-ATPase/ROS amplification loop has demonstrated significance in oxidative stress related disease states, including obesity, atherosclerosis, heart failure, uremic cardiomyopathy, and hypertension. The discovery of this novel oxidative stress signaling pathway, holds significant therapeutic potential for the aforementioned conditions and others that are rooted in ROS. Full article
(This article belongs to the Special Issue Cardiotonic Steroids)
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