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Nature Metabolism Nov 2019Senescence is a cellular stress response that results in the stable arrest of old, damaged or preneoplastic cells. Oncogene-induced senescence is tumor suppressive but...
Senescence is a cellular stress response that results in the stable arrest of old, damaged or preneoplastic cells. Oncogene-induced senescence is tumor suppressive but can also exacerbate tumorigenesis through the secretion of pro-inflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed senolytics, have proved beneficial in animal models of many age-associated diseases. Here, we show that the cardiac glycoside, ouabain, is a senolytic agent with broad activity. Senescent cells are sensitized to ouabain-induced apoptosis, a process mediated in part by induction of the pro-apoptotic Bcl2-family protein NOXA. We show that cardiac glycosides synergize with anti-cancer drugs to kill tumor cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent preneoplastic cells. Our findings suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanism. Given the broad range of senescent cells targeted by cardiac glycosides their use against age-related diseases warrants further exploration.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cardiac Glycosides; Cellular Senescence; Humans; Mice; Ouabain; Quercetin; Rats
PubMed: 31799499
DOI: 10.1038/s42255-019-0122-z -
Cell Death & Disease Mar 2021Chemotherapeutic agents have been linked to immunogenic cell death (ICD) induction that is capable of augmenting anti-tumor immune surveillance. The cardiac glycoside...
Chemotherapeutic agents have been linked to immunogenic cell death (ICD) induction that is capable of augmenting anti-tumor immune surveillance. The cardiac glycoside oleandrin, which inhibits Na/K-ATPase pump (NKP), has been shown to suppress breast cancer growth via inducing apoptosis. In the present study, we showed that oleandrin treatment triggered breast cancer cell ICD by inducing calreticulin (CRT) exposure on cell surface and the release of high-mobility group protein B1 (HMGB1), heat shock protein 70/90 (HSP70/90), and adenosine triphosphate (ATP). The maturation and activation of dendritic cells (DCs) were increased by co-culturing with the oleandrin-treated cancer cells, which subsequently enhanced CD8 T cell cytotoxicity. Murine breast cancer cell line EMT6 was engrafted into BALB/c mice, and tumor-bearing mice were administered with oleandrin intraperitoneally every day. Oleandrin inhibited tumor growth and increased tumor infiltrating lymphocytes including DCs and T cells. Furthermore, the differential mRNA expression incurred by oleandrin was investigated by mRNA sequencing and subsequently confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Mechanistically, oleandrin induced endoplasmic reticulum (ER) stress-associated, caspase-independent ICD mainly through PERK/elF2α/ATF4/CHOP pathway. Pharmacological and genetic inhibition of protein kinase R-like ER kinase (PERK) suppressed oleandrin-triggered ICD. Taken together, our findings showed that oleandrin triggered ER stress and induced ICD-mediated immune destruction of breast cancer cells. Oleandrin combined with immune checkpoint inhibitors might improve the efficacy of immunotherapy.
Topics: Activating Transcription Factor 4; Animals; Breast Neoplasms; Cardenolides; Cardiac Glycosides; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Immunogenic Cell Death; Mice
PubMed: 33762577
DOI: 10.1038/s41419-021-03605-y -
International Journal of Molecular... Mar 2022Among carbohydrate active enzymes, glycoside phosphorylases (GPs) are valuable catalysts for white biotechnologies, due to their exquisite capacity to efficiently... (Review)
Review
Among carbohydrate active enzymes, glycoside phosphorylases (GPs) are valuable catalysts for white biotechnologies, due to their exquisite capacity to efficiently re-modulate oligo- and poly-saccharides, without the need for costly activated sugars as substrates. The reversibility of the phosphorolysis reaction, indeed, makes them attractive tools for glycodiversification. However, discovery of new GP functions is hindered by the difficulty in identifying them in sequence databases, and, rather, relies on extensive and tedious biochemical characterization studies. Nevertheless, recent advances in automated tools have led to major improvements in GP mining, activity predictions, and functional screening. Implementation of GPs into innovative in vitro and in cellulo bioproduction strategies has also made substantial advances. Herein, we propose to discuss the latest developments in the strategies employed to efficiently discover GPs and make the best use of their exceptional catalytic properties for glycoside bioproduction.
Topics: Biotechnology; Cardiac Glycosides; Catalysis; Glycoside Hydrolases; Glycosides; Phosphorylases
PubMed: 35328479
DOI: 10.3390/ijms23063043 -
Investigative Ophthalmology & Visual... May 2020Mutations in the RS1 gene, which encodes retinoschisin, cause X-linked juvenile retinoschisis, a retinal dystrophy in males. Retinoschisin specifically interacts with...
PURPOSE
Mutations in the RS1 gene, which encodes retinoschisin, cause X-linked juvenile retinoschisis, a retinal dystrophy in males. Retinoschisin specifically interacts with the retinal sodium-potassium adenosine triphosphatase (Na/K-ATPase), a transmembrane ion pump. Na/K-ATPases also bind cardiac glycosides, which control the activity of the pump and have been linked to disturbances in retinal homeostasis. In this study, we investigated the crosstalk between retinoschisin and cardiac glycosides at the retinal Na/K-ATPase and the consequences of this interplay on retinal integrity.
METHODS
The effect of cardiac glycosides (ouabain and digoxin) on the binding of retinoschisin to the retinal Na/K-ATPase was investigated via western blot and immunocytochemistry. Also, the influence of retinoschisin on the binding of cardiac glycosides was analyzed via enzymatic assays, which quantified cardiac glycoside-sensitive Na/K-ATPase pump activity. Moreover, retinoschisin-dependent binding of tritium-labeled ouabain to the Na/K-ATPase was determined. Finally, a reciprocal effect of retinoschisin and cardiac glycosides on Na/K-ATPase localization and photoreceptor degeneration was addressed using immunohistochemistry in retinoschisin-deficient murine retinal explants.
RESULTS
Cardiac glycosides displaced retinoschisin from the retinal Na/K-ATPase; however, retinoschisin did not affect cardiac glycoside binding. Notably, cardiac glycosides reduced the capacity of retinoschisin to regulate Na/K-ATPase localization and to protect against photoreceptor degeneration.
CONCLUSIONS
Our findings reveal opposing effects of retinoschisin and cardiac glycosides on retinal Na/K-ATPase binding and on retinal integrity, suggesting that a fine-tuned interplay between both components is required to maintain retinal homeostasis. This observation provides new insight into the mechanisms underlying the pathological effects of cardiac glycoside treatment on retinal integrity.
Topics: Animals; Cells, Cultured; Digoxin; Disease Models, Animal; Eye Proteins; Humans; Immunohistochemistry; Mice, Inbred C57BL; Ouabain; Protein Binding; Retinoschisis; Signal Transduction; Sodium-Potassium-Exchanging ATPase
PubMed: 32392309
DOI: 10.1167/iovs.61.5.1 -
Toxins May 2021Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and... (Review)
Review
Cardiac glycosides (CGs), toxins well-known for numerous human and cattle poisoning, are natural compounds, the biosynthesis of which occurs in various plants and animals as a self-protective mechanism to prevent grazing and predation. Interestingly, some insect species can take advantage of the CG's toxicity and by absorbing them, they are also protected from predation. The mechanism of action of CG's toxicity is inhibition of Na/K-ATPase (the sodium-potassium pump, NKA), which disrupts the ionic homeostasis leading to elevated Ca concentration resulting in cell death. Thus, NKA serves as a molecular target for CGs (although it is not the only one) and even though CGs are toxic for humans and some animals, they can also be used as remedies for various diseases, such as cardiovascular ones, and possibly cancer. Although the anticancer mechanism of CGs has not been fully elucidated, yet, it is thought to be connected with the second role of NKA being a receptor that can induce several cell signaling cascades and even serve as a growth factor and, thus, inhibit cancer cell proliferation at low nontoxic concentrations. These growth inhibitory effects are often observed only in cancer cells, thereby, offering a possibility for CGs to be repositioned for cancer treatment serving not only as chemotherapeutic agents but also as immunogenic cell death triggers. Therefore, here, we report on CG's chemical structures, production optimization, and biological activity with possible use in cancer therapy, as well as, discuss their antiviral potential which was discovered quite recently. Special attention has been devoted to digitoxin, digoxin, and ouabain.
Topics: Animals; Antineoplastic Agents; Cardiac Glycosides; Cattle; Digitoxin; Digoxin; Humans; Molecular Targeted Therapy; Neoplasms; Ouabain; Sodium-Potassium-Exchanging ATPase
PubMed: 34064873
DOI: 10.3390/toxins13050344 -
Planta Medica Aug 2017This review provides a renewed look at the genus . Emphasis will be put on those issues that attracted the most attention or even went through paradigmatic changes since... (Review)
Review
This review provides a renewed look at the genus . Emphasis will be put on those issues that attracted the most attention or even went through paradigmatic changes since the turn of the millennium. PubMed and Google Scholar were used ("" and "Foxglove" were the key words) to identify research from 2000 till 2017 containing data relevant enough to be presented here. Intriguing new results emerged from studies related to the phylogeny and taxonomy of the genus as well as to the biosynthesis and potential medicinal uses of the key active compounds, the cardiac glycosides. Several Eastern and Western Foxgloves were studied with respect to their propagation In this context, molecular biology tools were applied and phytochemical analyses were conducted. Structure elucidation and analytical methods, which have experienced less exciting progress, will not be considered here in great detail.
Topics: Cardiac Glycosides; Digitalis; Phytochemicals; Plant Extracts; Plants, Medicinal
PubMed: 28561136
DOI: 10.1055/s-0043-111240 -
Nature Communications Oct 2019Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions....
Compounds with specific cytotoxic activity in senescent cells, or senolytics, support the causal involvement of senescence in aging and offer therapeutic interventions. Here we report the identification of Cardiac Glycosides (CGs) as a family of compounds with senolytic activity. CGs, by targeting the Na+/K+ATPase pump, cause a disbalanced electrochemical gradient within the cell causing depolarization and acidification. Senescent cells present a slightly depolarized plasma membrane and higher concentrations of H+, making them more susceptible to the action of CGs. These vulnerabilities can be exploited for therapeutic purposes as evidenced by the in vivo eradication of tumors xenografted in mice after treatment with the combination of a senogenic and a senolytic drug. The senolytic effect of CGs is also effective in the elimination of senescence-induced lung fibrosis. This experimental approach allows the identification of compounds with senolytic activity that could potentially be used to develop effective treatments against age-related diseases.
Topics: A549 Cells; Animals; Antibiotics, Antineoplastic; Apoptosis; Bleomycin; Breast Neoplasms; Cardiac Glycosides; Cell Line, Tumor; Cell Membrane; Cellular Senescence; Chondrocytes; Digoxin; Female; Fibroblasts; Humans; Hydrogen-Ion Concentration; Mice; Osteoarthritis; Ouabain; Proscillaridin; Pulmonary Fibrosis; Xenograft Model Antitumor Assays
PubMed: 31636264
DOI: 10.1038/s41467-019-12888-x -
Molecules (Basel, Switzerland) Nov 2017Cardiac glycosides (CGs) are natural compounds widely used in the treatment of several cardiac conditions and more recently have been recognized as potential antitumor... (Review)
Review
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.
Topics: Animals; Antineoplastic Agents; Cardiac Glycosides; Humans; Immunologic Factors; Neoplasms; Sodium-Potassium-Exchanging ATPase
PubMed: 29117117
DOI: 10.3390/molecules22111932 -
International Journal of Cancer Mar 2017Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of... (Meta-Analysis)
Meta-Analysis Review
Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta-analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta-analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, nine studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR = 1.34; 95% CI 1.25, 1.44; p < 0.001) with little variation in the association between studies (I = 16%, p for heterogeneity = 0.30). Results were little altered when analysis was restricted to studies with high quality scores or cohort studies. Overall, there was a 34% increase in breast risk with use of cardiac glycosides but it is unclear whether this association reflects confounding or is causal. Further observational studies are required to examine this association particularly for estrogen receptor positive breast cancer and to explore the role of potential confounding variables.
Topics: Breast Neoplasms; Cardiac Glycosides; Causality; Cohort Studies; Confidence Intervals; Confounding Factors, Epidemiologic; Estrogens; Female; Humans; Incidence; Models, Biological; Neoplasms, Hormone-Dependent; Observational Studies as Topic; Phytoestrogens; Registries; Risk Factors; Surveys and Questionnaires
PubMed: 27861859
DOI: 10.1002/ijc.30520 -
Current Biology : CB Nov 2021The community of plant-feeding insects (herbivores) that specialize on milkweeds (Apocynaceae) form a remarkable example of convergent evolution across levels of...
The community of plant-feeding insects (herbivores) that specialize on milkweeds (Apocynaceae) form a remarkable example of convergent evolution across levels of biological organization. In response to toxic cardiac glycosides produced by these plants, the monarch butterfly (Danaus plexippus) and other specialist herbivores have evolved parallel substitutions in the alpha subunit (ATPA) of the Na/K-ATPase. These substitutions render the pump insensitive to cardiac glycosides, allowing the monarch and other specialists, from aphids to beetles, to sequester cardiac glycosides, which in turn provide defense against attacks by enemies from the third trophic level. The evolution of 'target-site-insensitivity' substitutions in these herbivores poses a fundamental biological question: have predators and parasitoids that feed on cardiac-glycoside-sequestering insects also evolved Na/K-ATPases that are similarly insensitive to cardiac glycosides (as predicted by Whiteman and Mooney)? In other words, can plant toxins cause evolutionary cascades that reach the third trophic level? Here we show that at least four enemies of the monarch and other milkweed herbivores have indeed evolved amino-acid substitutions associated with target-site insensitivity to cardiac glycosides. These attackers represent four major animal clades, implicating cardiac glycosides as keystone molecules and establishing ATPalpha, which encodes ATPA, as a keystone gene with effects that reverberate within ecological communities.
Topics: Animals; Asclepias; Butterflies; Cardenolides; Cardiac Glycosides; Herbivory; Insecta; Parasites; Plants; Sodium-Potassium-Exchanging ATPase
PubMed: 34813747
DOI: 10.1016/j.cub.2021.10.025