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Frontiers in Pharmacology 2023Calotropin is a pharmacologically active compound isolated from milkweed plants like and that belong to the Asclepiadaceae family. All of these plants are recognised... (Review)
Review
Calotropin is a pharmacologically active compound isolated from milkweed plants like and that belong to the Asclepiadaceae family. All of these plants are recognised as medical traditional plants used in Asian countries. Calotropin is identified as a highly potent cardenolide that has a similar chemical structure to cardiac glycosides (such as digoxin and digitoxin). During the last few years, cytotoxic and antitumor effects of cardenolides glycosides have been reported more frequently. Among cardenolides, calotropin is identified as the most promising agent. In this updated and comprehensive review, we aimed to analyze and discuss the specific mechanisms and molecular targets of calotropin in cancer treatment to open new perspectives for the adjuvant treatment of different types of cancer. The effects of calotropin on cancer have been extensively studied in preclinical pharmacological studies using cancer cell lines and in experimental animal models that have targeted antitumor mechanisms and anticancer signaling pathways. The analyzed information from the specialized literature was obtained from scientific databases until December 2022, mainly from PubMed/MedLine, Google Scholar, Scopus, Web of Science, and Science Direct databases using specific MeSH search terms. The results of our analysis demonstrate that calotropin can be a potential chemotherapeutic/chemopreventive adjunctive agent in cancer pharmacotherapeutic management.
PubMed: 37138852
DOI: 10.3389/fphar.2023.1160616 -
Biochimica Et Biophysica Acta. General... Nov 2020Cardiac glycosides (CGs), such as digitoxin, are traditionally used for treatment of congestive heart failure; recently they also gained attention for their anticancer...
BACKGROUND
Cardiac glycosides (CGs), such as digitoxin, are traditionally used for treatment of congestive heart failure; recently they also gained attention for their anticancer properties. Previous studies showed that digitoxin and a synthetic L-sugar monosaccharide analog treatment decreases cancer cell proliferation, increases apoptosis, and pro-adhesion abilities; however, no reports are available on their potential to alter lung cancer cell cytoskeleton structure and reduce migratory ability. Herein, we investigated the anticancer effects of digitoxin and its analog, digitoxigenin-α-L-rhamnoside (D6MA), to establish whether cytoskeleton reorganization and reduced motility are drug-induced cellular outcomes.
METHODS
We treated non-small cell lung carcinoma cells (NSCLCs) with sub-therapeutic, therapeutic, and toxic concentrations of digitoxin and D6MA respectively, followed by both single point and real-time assays to evaluate changes in cellular gene and protein expression, adhesion, elasticity, and migration.
RESULTS
Digitoxin and D6MA induced a decrease in matrix metalloproteinases expression via altered focal adhesion signaling and a suppression of the phosphoinositide 3-kinases / protein kinase B pathway which lead to enhanced adhesion, altered elasticity, and reduced motility of NSCLCs. Global gene expression analysis identified dose-dependent changes to nuclear factor kappa-light-chain-enhancer, epithelial tumor, and microtubule dynamics signaling.
CONCLUSIONS
Our study demonstrates that digitoxin and D6MA can target antitumor signaling pathways to alter NSCLC cytoskeleton and migratory ability to thus potentially reduce their tumorigenicity.
SIGNIFICANCE
Discovering signaling pathways that control cancer's cell phenotype and how such pathways are affected by CG treatment will potentially allow for active usage of synthetic CG analogs as therapeutic agents in advanced lung conditions.
Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cytoskeleton; Digitoxin; Humans; Lung Neoplasms
PubMed: 32679249
DOI: 10.1016/j.bbagen.2020.129683 -
Inhibitory Effects of Digoxin and Digitoxin on Cell Growth in Human Ovarian Cancer Cell Line SKOV-3.Integrative Cancer Therapies 2021Cardiac glycosides (CGs) possess a chemical structure similar to steroids, and are inhibitors of the sodium potassium pump. An anti-tumor effect of CGs in breast and...
BACKGROUND
Cardiac glycosides (CGs) possess a chemical structure similar to steroids, and are inhibitors of the sodium potassium pump. An anti-tumor effect of CGs in breast and prostate cancers has been reported, but the effect of CGs on ovarian cancer is still unclear.
AIMS
In this study, the effects of CGs on proliferation, cytotoxicity and cell cycle of ovarian cancer cell line (SKOV-3) have been investigated.
PROCEDURE
The cell proliferation and cytotoxicity were detected by MTT assay and LDH activity assay, respectively. CGs, at concentrations higher than IC50, decreased cell proliferation and showed increased cytotoxicity toward SKOV-3 cells. The colony-formation ability was reduced after treatment with digoxin and digitoxin for 10 days. Furthermore, we explored the effect of digoxin and digitoxin on the distribution of cell cycle by flow cytometry.
RESULTS
Results revealed that both digoxin and digitoxin led to cell cycle arrest in G/G phase with 24 or 48 hours, but the arrest of G/G phase was not observed at 72 hours. We evaluated the percentage of hypodiploid cell population as an index of the cellular fragments through flow cytometry. The data indicated that cellular fragments were significantly increased by treating with digitoxin at the concentrations of IC50 and 10 M for 72 hours.
CONCLUSION
Taken together, these data suggest that CGs decreased cell proliferation and increased cytotoxicity through cell cycle arrest at the G/G phase. CGs have anti-tumor effect in SKOV-3 cells and might be a potential therapeutic drug for ovarian cancer. Since this study is a preliminary investigation of CGs on SKOV-3 cells, more experiments might be performed in the future. Furthermore, more ovarian cancer cell lines might also be employed in the future studies to confirm the effect of CGs in ovarian cancer.
Topics: Cell Cycle; Cell Line; Cell Proliferation; Digitoxin; Digoxin; Female; Humans; Male; Ovarian Neoplasms
PubMed: 33736483
DOI: 10.1177/15347354211002662 -
Scandinavian Cardiovascular Journal :... Dec 2022. The study sought to assess the prognostic value of treatment with digitalis on long-term prognosis in patients with ventricular tachyarrhythmias and atrial...
. The study sought to assess the prognostic value of treatment with digitalis on long-term prognosis in patients with ventricular tachyarrhythmias and atrial fibrillation (AF) and/or heart failure (HF). . Data regarding the outcome of digitalis therapy following ventricular tachyarrhythmias is limited. A large retrospective registry was used including consecutive patients with episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2015. Patients treated with digitalis were compared to patients without. The primary prognostic endpoint was all-cause mortality at 3 years, secondary endpoints comprised a composite arrhythmic endpoint (i.e. recurrences of ventricular tachyarrhythmias, appropriate implantable cardioverter defibrillator (ICD) therapies, sudden cardiac death) and cardiac rehospitalization. Kaplan Mayer survival curves, multivariable cox regression, and time trend analyses were applied for statistics. Eight hundred and thirty-one patients were included (20% treated with digitalis and 80% without). At 3 years, digitalis treatment was not associated with all-cause mortality following ventricular tachyarrhythmias (24 21%, log-rank = .736; HR = 1.063; 95% CI 0.746-1.515; = .736). However, digitalis therapy was associated with an increased risk of the composite arrhythmic endpoint (38 23%; log-rank = .001; HR = 1.719; 95% CI 1.279-2.311; = .001) and cardiac rehospitalization (31 18%; log-rank = .001; HR = 1.829; 95% CI 1.318-2.538; = .001), which was still evident within multivariable Cox regression analyses. Finally, digitoxin may be associated with a worse prognosis than digoxin. Digitalis therapy was not associated with mortality in patients with ventricular tachyarrhythmias, but with increased risk of the composite arrhythmic endpoint and cardiac rehospitalization at 3 years.
Topics: Death, Sudden, Cardiac; Digitalis; Digitoxin; Humans; Retrospective Studies; Tachycardia, Ventricular
PubMed: 35792713
DOI: 10.1080/14017431.2022.2091793 -
Clinical Research in Cardiology :... Aug 2023The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial.
METHODS AND RESULTS
In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5-23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m, and BMI < 27 kg/m each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively.
CONCLUSION
In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m, BMI < 27 kg/m, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.
Topics: Humans; Female; Aged; Heart Failure; Digitoxin; Stroke Volume; ROC Curve; Sensitivity and Specificity
PubMed: 37087503
DOI: 10.1007/s00392-023-02199-z -
Frontiers in Molecular Biosciences 2023Digitoxin is a cardiac glycoside used to treat heart failure and heart arrhythmia. However, its therapeutic concentration range is very narrow. High doses of digitoxin...
Digitoxin is a cardiac glycoside used to treat heart failure and heart arrhythmia. However, its therapeutic concentration range is very narrow. High doses of digitoxin are associated with severe side effects; therefore, it is necessary to develop the delivery system which can control the plasma levels of it. In this context, the binding of lysozyme, an important protein having many applications, with digitoxin has been studied to see the ability of the former as a carrier. The studies were carried out using both experimental and computational methods. The intrinsic fluorescence of lysozyme increased on the addition of digitoxin. Fluorescence results suggested that there was a strong interaction between lysozyme and digitoxin which was favored, mainly, by hydrophobic forces. Further, digitoxin affected the secondary structure of lysozyme slightly by causing the partial unfolding of lysozyme. The preferred binding site of digitoxin within lysozyme was the large cavity of the protein. Molecular docking studies also established the principal role of hydrophobic forces in the binding with a significant support of hydrogen bonding. Frontier molecular orbitals of free digitoxin and in complexation with lysozyme were also computed and discussed. The findings from molecular dynamics simulation studies elucidate that, when contrasted with the first and third conformations of the digitoxin-bound lysozyme complex, the second conformation promotes structural stability, reduces flexibility, and enhances the compactness and folding properties of lysozyme. The overall study shows that lysozyme could act as a potential carrier for digitoxin in pharmaceutical formulations.
PubMed: 38187092
DOI: 10.3389/fmolb.2023.1327740 -
Journal of Cardiovascular Pharmacology... May 2020We previously showed that digitoxin prolongs the survival of rats with heart failure due to myocardial infarction (MI). In this study, we evaluated the effect of...
We previously showed that digitoxin prolongs the survival of rats with heart failure due to myocardial infarction (MI). In this study, we evaluated the effect of digitoxin on myocardial structure, ventricular function, and proteins involved in calcium kinetics. Seventy-two rats with MI >35% of the left ventricle were randomly assigned to 4 treatment groups: sham (n = 15), digitoxin (n = 11), infarction (n = 20), and infarction + digitoxin (n = 26). The rats were assessed 120 days after surgery by echocardiogram, hemodynamics, papillary muscle mechanics, collagen content, cardiomyocyte nuclear volume, and Western blot analysis of proteins involved in calcium kinetics. Digitoxin was administered via the rat chow. Two-way analysis of variance was used for comparisons. Myocardial infarction caused inotropic impairment, pulmonary congestion, increase of nuclear volume, myocardial collagen, and Na/Ca2 exchanger levels, and decreased SERCA2 and phosphorylated phospholamban levels. Treatment with digitoxin showed improvements in cardiac remodeling, inotropism, ventricular performance, pulmonary congestion, collagen accumulation, nuclear volume, and proteins involved in calcium kinetics. In rats with heart failure due to MI, long-term treatment with digitoxin attenuates congestive heart failure, mitigates myocardial remodeling and contractile impairment, and preserves myocardial levels of proteins involved in calcium kinetics.
Topics: Animals; Calcium; Calcium Signaling; Calcium-Binding Proteins; Cardiotonic Agents; Digitoxin; Disease Models, Animal; Female; Heart Failure; Hypertrophy, Left Ventricular; Kinetics; Myocardial Contraction; Myocardial Infarction; Myocardium; Rats, Wistar; Ventricular Function, Left; Ventricular Remodeling
PubMed: 31714152
DOI: 10.1177/1074248419887708 -
Molecules (Basel, Switzerland) Sep 2021Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being... (Review)
Review
Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being tested has already been approved for another condition. One example of drug repositioning involves cardiac glycosides (CGs), which have, for a long time, been used in heart medicine. Moreover, it has been known for decades that CGs also have great potential in cancer treatment and, thus, many clinical trials now evaluate their anticancer potential. Interestingly, heart failure and cancer are not the only conditions for which CGs could be effectively used. In recent years, the antiviral potential of CGs has been extensively studied, and with the ongoing SARS-CoV-2 pandemic, this interest in CGs has increased even more. Therefore, here, we present CGs as potent and promising antiviral compounds, which can interfere with almost any steps of the viral life cycle, except for the viral attachment to a host cell. In this review article, we summarize the reported data on this hot topic and discuss the mechanisms of antiviral action of CGs, with reference to the particular viral life cycle phase they interfere with.
Topics: Antiviral Agents; COVID-19; Cardiac Glycosides; Digitoxin; Digoxin; Drug Repositioning; Heart Failure; Humans; Neoplasms; Ouabain; Pandemics; SARS-CoV-2; Sodium-Potassium-Exchanging ATPase; Virus Internalization; Virus Replication
PubMed: 34577097
DOI: 10.3390/molecules26185627 -
International Immunopharmacology Feb 2024Rheumatoid arthritis (RA) is an autoimmune disease that affects joints, causing inflammation, synovitis, and erosion of cartilage and bone. Periplogenin is an active...
Rheumatoid arthritis (RA) is an autoimmune disease that affects joints, causing inflammation, synovitis, and erosion of cartilage and bone. Periplogenin is an active ingredient in the anti-rheumatic and anti-inflammatory herb, cortex periplocae. We conducted a study using a CIA model and an in vitro model of fibroblast-like synoviocytes (FLS) induced by Tumor Necrosis Factor-alpha (TNF-α) stimulation. We evaluated cell activity, proliferation, and migration using the CCK8 test, EDU kit, and transwell assays, as well as network pharmacokinetic analysis of periplogenin targets and RA-related effects. Furthermore, we measured inflammatory factors and matrix metalloproteinases (MMPs) expression using ELISA and qRT-PCR assays. We also evaluated joint destruction using HE and Safranin O-Fast Green Staining and examined the changes in the JAK2/3-STAT3 pathway using western blot. The results indicated that periplogenin can effectively inhibit the secretion of inflammatory factors, suppress the JAK2/3-STAT3 pathway, and impede the proliferation and migration of RA FLS. Thus, periplogenin alleviated the Synovial inflammatory infiltration of RA.
Topics: Humans; Animals; Arthritis, Rheumatoid; Synoviocytes; Inflammation; Cell Proliferation; Fibroblasts; Synovial Membrane; Cells, Cultured; Arthritis, Experimental; Janus Kinase 2; STAT3 Transcription Factor; Digitoxigenin
PubMed: 38183911
DOI: 10.1016/j.intimp.2024.111487 -
International Journal of Molecular... Jul 2022Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the...
Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1-100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Digitoxin; Humans; Pancreatic Neoplasms; Phenotype; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species
PubMed: 35897809
DOI: 10.3390/ijms23158237