digoxin and Neoplasms

The goal of this paper is to review the impact of marketed oral anticancer agents on the pharmacokinetics of co-administered medications in humans focusing on clinically relevant interactions.. We identified the oral anticancer agents marketed in the United States and in Europe as December 31, 2021. Based on prescription information and literature, we selected the agents that were moderate/strong inducers or inhibitors of pharmacokinetic human molecular determinants of pharmacological interest (enzymes, drug transporters) highlighting on clinically meaningful interactions (i.e., at least a 2-fold variation in exposure of the comedication, excepting 1.5 for digoxin).. As December 31, 2021, 125 marketed oral anticancer agents were identified. Based on a≥2-fold exposure change (≥ 1.5 for digoxin), 24 oral anticancer agents commercialised in the European Union and the United States are susceptible to generate clinically meaningful pharmacokinetic interactions with comedications. All are recent agents and most of them (19/24) are indicated in the treatment of solid tumours. In all, 32 interactions with human molecular kinetic determinants were found for the 24 agents. Most of the pharmacokinetic interactions (26/32) are driven through cytochrome P450 (CYP) inhibition or induction, CYP3A4 being the major contributor (15).. 24 anticancer agents (20% of the oral market) have the potential to significantly interact with co-administered drugs. These potential pharmacokinetic interactions are likely to occur in the ambulatory setting in a polymedicated and aged population, needing to reinforce the vigilance of community pharmacists and health care providers (particularly in thoracic oncology and genitourinary cancer) with these sometimes rarely prescribed agents.

Topics: Aged; Antineoplastic Agents; Cytochrome P-450 Enzyme System; Digoxin; Drug Interactions; Humans; Neoplasms

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; Cardiac Glycosides; COVID-19; Digitoxin; Digoxin; Drug Repositioning; Heart Failure; Humans; Neoplasms; Ouabain; Pandemics; SARS-CoV-2; Sodium-Potassium-Exchanging ATPase; Virus Internalization; Virus Replication

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Digoxin-like immunoreactive factor (DLIF) and ouabain-like factor (OLF) are the mammalian counterparts to the plant-derived cardiotonic steroids digoxin and ouabain. Compelling evidence indicates that the cardiotonic steroids may have anticancer properties. Recent evidence indicates that low (nanomolar) concentrations of DLIF selectively induce cell death in transformed cells, while sparing normal cells, and is even more potent than the plant-derived compounds. The discovery that these endogenous molecules may play a role in the regulation of cancer cell proliferation provides a potentially new paradigm for the physiologic role of DLIF and OLF. In addition, the possible use of digoxin itself as a therapeutic agent in cancer has been explored, and evidence suggests that its conversion to dihydrodigoxin may be involved in regulating anticancer activity. The mechanism(s) for the pro-apoptotic property of these compounds is not known. In this brief review, we will discuss the proposed mechanism of action of digoxin, ouabain, DLIF, and OLF as anticancer compounds and discuss the effects that metabolic conversion to their dihydro-derivatives may have on this activity. From the perspective of therapeutic drug monitoring, these findings suggest some potential new challenges in the need to measure concentrations of digoxin and dihydrodigoxin as well as their endogenous counterparts DLIF and OLF in serum.

Topics: Adrenal Glands; Animals; Anticarcinogenic Agents; Apoptosis; Cardenolides; Cell Proliferation; Digoxin; Humans; Neoplasms; Ouabain; Saponins

The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.

Topics: Animals; Anti-HIV Agents; Antidepressive Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; CD4 Lymphocyte Count; Digoxin; Epilepsy; Genotype; Haplotypes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney; Neoplasms; Organic Anion Transporters; RNA, Messenger

Cardiotonic steroids (CTS), long used to treat heart failure, are endogenously produced in mammals. Among them are the hydrophilic cardenolide ouabain and the more hydrophobic cardenolide digoxin, as well as the bufadienolides marinobufagenin and telecinobufagin. The physiological effects of endogenous ouabain on blood pressure and cardiac activity are consistent with the "Na(+)-lag" hypothesis. This hypothesis assumes that, in cardiac and arterial myocytes, a CTS-induced local increase of Na(+) concentration due to inhibition of Na(+)/K(+)-ATPase leads to an increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) via a backward-running Na(+)/Ca(2+) exchanger. The increase in [Ca(2+)](i) then activates muscle contraction. The Na(+)-lag hypothesis may best explain short-term and inotropic actions of CTS. Yet all data on the CTS-induced alteration of gene expression are consistent with another hypothesis, based on the Na(+)/K(+)-ATPase "signalosome," that describes the interaction of cardiac glycosides with the Na(+) pump as machinery activating various signaling pathways via intramembrane and cytosolic protein-protein interactions. These pathways, which may be activated simultaneously or selectively, elevate [Ca(2+)](i), activate Src and the ERK1/2 kinase pathways, and activate phosphoinositide 3-kinase and protein kinase B (Akt), NF-kappaB, and reactive oxygen species. A recent development indicates that new pharmaceuticals with antihypertensive and anticancer activities may be found among CTS and their derivatives: the antihypertensive rostafuroxin suppresses Na(+) resorption and the Src-epidermal growth factor receptor-ERK pathway in kidney tubule cells. It may be the parent compound of a new principle of antihypertensive therapy. Bufalin and oleandrin or the cardenolide analog UNBS-1450 block tumor cell proliferation and induce apoptosis at low concentrations in tumors with constitutive activation of NF-kappaB.

Topics: Animals; Antihypertensive Agents; Antineoplastic Agents; Blood Pressure; Bufanolides; Calcium; Cardiac Glycosides; Cardiovascular System; Cell Death; Cell Proliferation; Diabetes Mellitus; Digoxin; Humans; Hypertension; Molecular Structure; Myocardial Contraction; Myocytes, Cardiac; Neoplasms; Ouabain; Sodium Chloride; Sodium-Potassium-Exchanging ATPase; Structure-Activity Relationship

The recent observation that potent and sequence-specific gene silencing by injection of double-stranded RNA (dsRNA) has sparked the phenomenon known as "RNA interference" (RNAi) and has enabled the gene-specific knockdown of drug transport proteins and metabolizing enzymes. The application of small interfering RNAs (siRNAs) is broad and the potential for use as research tools is now well established in vitro. In vivo use is still a challenge that is primarily focused on the difficulty of delivering siRNAs to target cells. The potential use of siRNAs as therapeutic agents is also exciting and holds great promise for future. For the study of drug transporter function in absorption, distribution, metabolism and excretion (ADME) and in the treatment of diseases, siRNA offers a way to gather interpretable mechanistic data-a distinct advantage over the use of "specific" chemical inhibitors. This mini review provides background information on siRNA as well as examples of the use of siRNA as applied to drug transporters.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caco-2 Cells; Digoxin; Gene Targeting; Genetic Therapy; Humans; Luciferases, Renilla; Neoplasms; Nervous System Diseases; RNA Interference; RNA, Small Interfering; Transfection

The oral absorption of digoxin in tablet form has been reported to be reduced after cancer chemotherapy and radiation therapy because of cancer treatment-induced damage to the intestinal epithelium. We investigated possible differences in the effects of high-dose cancer chemotherapy on the relative bioavailability of digoxin administered in tablet form (Lanoxin; Burroughs Wellcome Co.) and in solution-in-capsule form (Lanoxicaps; Burroughs Wellcome Co.). Each subject received a single oral dose of either 0.5 mg Lanoxin (six subjects) or 0.4 mg Lanoxicaps (seven subjects) both before and after chemotherapy. For Lanoxin, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean +/- SD) of the value before chemotherapy (P = 0.02), whereas for Lanoxicaps there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. These findings show that changes in the oral dosage formulation of digoxin from a tablet to a solution-in-capsule form can overcome the adverse effects of high-dose cancer chemotherapy on drug absorption, and suggest a similar approach may be successful for other drugs.

Topics: Absorption; Administration, Oral; Adult; Antineoplastic Agents; Biological Availability; Capsules; Digoxin; Drug Administration Schedule; Female; Humans; Kinetics; Male; Middle Aged; Neoplasms; Radioimmunoassay; Random Allocation; Tablets

Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR (eGFRcys) is an alternative marker of GFR.. To determine whether the therapeutic drug levels and adverse events (AEs) associated with renally cleared medications were higher in patients with cancer whose eGFRcys was more than 30% lower than their eGFRcr.. This cohort study analyzed adult patients with cancer at 2 major academic cancer centers in Boston, Massachusetts. These patients had their creatinine and cystatin C measured on the same day between May 2010 and January 2022. The date of the first simultaneous eGFRcr and eGFRcys measurement was considered to be the baseline date.. The primary exposure was eGFR discordance, defined as an eGFRcys that was more than 30% lower than the eGFRcr.. The primary outcome was risk of the following medication-related AEs within 90 days of the baseline date: (1) supratherapeutic vancomycin trough level greater than 30 μg/mL, (2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5 mEq/L), (3) baclofen toxic effect, and (4) supratherapeutic digoxin level (>2.0 ng/mL). For the secondary outcome, a multivariable Cox proportional hazards regression model was used to compare 30-day survival of those with vs without eGFR discordance.. A total of 1869 adult patients with cancer (mean [SD] age, 66 [14] years; 948 males [51%]) had simultaneous eGFRcys and eGFRcr measurement. There were 543 patients (29%) with an eGFRcys that was more than 30% lower than their eGFRcr. Patients with an eGFRcys that was more than 30% lower than their eGFRcr were more likely to experience medication-related AEs compared with patients with concordant eGFRs (defined as eGFRcys within 30% of eGFRcr), including vancomycin levels greater than 30 μg/mL (43 of 179 [24%] vs 7 of 77 [9%]; P = .01), trimethoprim-sulfamethoxazole-related hyperkalemia (29 of 129 [22%] vs 11 of 92 [12%]; P = .07), baclofen toxic effects (5 of 19 [26%] vs 0 of 11; P = .19), and supratherapeutic digoxin levels (7 of 24 [29%] vs 0 of 10; P = .08). The adjusted odds ratio for vancomycin levels more than 30 μg/mL was 2.59 (95% CI, 1.08-7.03; P = .04). Patients with an eGFRcys more than 30% lower than their eGFRcr had an increased 30-day mortality (adjusted hazard ratio, 1.98; 95% CI, 1.26-3.11; P = .003).. Results of this study suggest that among patients with cancer with simultaneous assessment of eGFRcys and eGFRcr, supratherapeutic drug levels and medication-related AEs occurred more commonly in those with an eGFRcys more than 30% lower than their eGFRcr. Future prospective studies are needed to improve and personalize GFR estimation and medication dosing in patients with cancer.

Topics: Adult; Aged; Baclofen; Cohort Studies; Creatinine; Cystatin C; Digoxin; Glomerular Filtration Rate; Humans; Hyperkalemia; Male; Neoplasms; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Complete tumor eradication is the ultimate goal of cancer therapy. However, the majority of anticancer drugs cause nonimmunogenic cell death and only exert on-site anticancer activities. The intrinsic genomic instability of cancer allows for the persistence and later expansion of treatment-resistant clones after surviving a sort of Darwinian selection of chemotherapy. Additional incorporation of immunotherapy, which is robust and individualized could be game-changing. Herein, we report a combination strategy that delivers nonimmunogenic cell death inducer Cisplatin to treat primary tumors and converts the tumor cells into vaccines that spurs a long-lasting immune response against residual tumors to prevent tumor recurrence and metastasis. Cisplatin(IV) prodrug was linked to the

Topics: Animals; Antineoplastic Agents; Cancer Vaccines; CD8-Positive T-Lymphocytes; Cell Death; Cell Proliferation; Cisplatin; Combined Modality Therapy; Digoxin; Genomic Instability; Humans; Immunity, Cellular; Methacrylates; Mice; Neoplasms

Digitoxin and digoxin are plant-derived cardiac glycosides. They are Na

Topics: Cardiac Glycosides; Digoxin; Humans; Membrane Proteins; Neoplasms; Reactive Oxygen Species; Sodium-Potassium-Exchanging ATPase; Voltage-Dependent Anion Channels

Topics: Antineoplastic Agents; Camptothecin; Digoxin; Flavonoids; Humans; Hypoxia-Inducible Factor 1; Mustard Compounds; Neoplasms; Oligonucleotides; Phenylpropionates; Polyethylene Glycols; Topotecan

In-vitro studies have suggested that the antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study. The study population consists of 78,615 men originally identified for the Finnish Randomized Study of Screening for Prostate Cancer. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used the Cox regression method to analyze separately overall cancer mortality and mortality from the most common types of cancer. During the median follow-up of 17.0 years after the baseline 28,936 (36.8%) men died, of these 8,889 due to cancer. 9,023 men (11.5%) had used antiarrhythmic drugs. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.43, 95% CI 1.34-1.53). Similar results were observed separately for digoxin and for sotalol. However, the risk associations disappeared in long-term use and were modified by background co-morbidities. All in all, cancer mortality was elevated among antiarrhythmic drug users. This association is probably non-causal as it was related to short-term use and disappeared in long-term use. Our results do not support the anticancer effects of digoxin or any other antiarrhythmic drug.

Topics: Aged; Anti-Arrhythmia Agents; Databases, Factual; Digoxin; Finland; Humans; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sotalol

Heart failure (HF) is the leading cause of death in the world and digoxin remains one of the oldest therapies for HF. However, its safety and efficacy have been controversial since its initial use and there is uncertainty about its long-term efficacy and safety. Recently, the repositioning of cardiac glycosides is to function in anti-tumor activity via multiple working pathways. It is interesting to compare the potential effects of digoxin in clinical patients and cell lines. First, we analyze patient information retrieved from the National Health Insurance Research database of Taiwan between January 1, 2000 and December 31, 2000. This retrospective study included a study cohort (1,219 patients) and a comparison cohort. Our analytical data suggested that patients taking digoxin are at an increased risk of cancers, including breast, liver, and lung cancers, during the 10-year follow-up period. In contrast to the anti-tumor function of digoxin, we further examined the potential pathway of digoxin via the cell-based strategy using several breast cancer cell lines, including MCF-7, BT-474, MAD-MB-231, and ZR-75-1. Digoxin consistently exerted its cytotoxicity to these four cell lines with various range of concentration. However, the proliferation of ZR-75-1 cells was the only cell lines induced by digoxin and the others were dramatically suppressed by digoxin. The responsiveness of SRSF3 to digoxin might be involved with cell-type differences. In summary, we combined a cohort study for digoxin treatment for HF patients with a cell-based strategy that addresses the translation issue, which revealed the complexity of personalized medicine.

Topics: Adult; Aged; Cell Survival; Comorbidity; Digoxin; Female; Follow-Up Studies; Heart Failure; Humans; Male; Middle Aged; Neoplasms; Odds Ratio; Precision Medicine; Risk; Socioeconomic Factors

The Na+-K+-ATPase is specifically inhibited by cardiac glycosides, some of which may also function as endogenous mammalian hormones. Previous studies using Xenopus oocytes, yeast cells, or purified isoforms demonstrated that affinities of various cardiac glycosides for three isoforms of the Na+-K+-ATPase (α1-α3β1) may differ, a finding with potential clinical implication. The present study investigates isoform selectivity and effects of cardiac glycosides on cultured mammalian cells under more physiological conditions. H1299 cells (non-small cell lung carcinoma) were engineered to express only one α-isoform (α1, α2, or α3) by combining stable transfection of isoforms and silencing endogenous α1. Cardiac glycoside binding was measured by displacement of bound 3H-ouabain. The experiments confirm moderate α1/α3:α2 selectivity of ouabain, moderate α2:α1 selectivity of digoxin, and enhanced α2:α1 selectivity of synthetic derivatives (Katz A, Tal DM, Heller D, Haviv H, Rabah B, Barkana Y, Marcovich AL, Karlish SJD. J Biol Chem 289: 21153-21162, 2014). Relative α2:α1 selectivity of digoxin vs. ouabain was also manifested by enhanced internalization of α2 in response to digoxin. Cellular proliferation assays of H1299 cells confirmed the patterns of α2:α1 selectivity for ouabain, digoxin, and a synthetic derivative and reveal a crucial role of surface pump density on sensitivity to cardiac glycosides. Because cardiac glycosides are being considered as drugs for treatment of cancer, effects of ouabain on proliferation of 12 cancer and noncancer cell lines, with variable plasma membrane expression of α1, have been tested. These demonstrated that sensitivity to ouabain indeed depends linearly on the plasma membrane surface density of Na+-K+-ATPase irrespective of status, malignant or nonmalignant.

Topics: Antineoplastic Agents; Binding, Competitive; Cardiac Glycosides; Cell Line, Tumor; Cell Proliferation; Digoxin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Isoenzymes; Neoplasms; Ouabain; Protein Binding; RNA Interference; Sodium-Potassium-Exchanging ATPase; Transfection

The signaling characteristics of Na(+)/K(+)-ATPase are distinct from its ion pumping activity. Cardiac glycosides modulate the Na(+)/K(+)-ATPase protein complex upon binding, activate downstream signaling pathways and increase [Ca(2+)]i. Recent studies demonstrate that the depletion of p53 and hypoxia-induced factor 1α proteins is caused by cardiac glycosides. However, the detailed mechanisms governing this process are not well known. In this study, we showed that the depletion of p53 proteins by digoxin involved not only inhibition of protein synthesis but also inhibition at the post-transcriptional level. Post-transcriptional regulation occurs via down-regulation of SRSF3, the primary splicing factor responsible for the switch from p53α to the p53β isoform. Digoxin also modulated G2/M arrest, DNA damage and apoptosis through the p53-dependent pathway in HeLa cells. In addition, digoxin was involved in epithelial-mesenchymal-transition progression via E-cadherin reduction and snail induction. Digoxin had similar effects to caffeine, another SRSF3-reduced agent, on the cell cycle profile and DNA damage of cells. Interestingly, combined digoxin and caffeine treatment blocked cell cycle progression and conferred resistance to cell death via snail induction. These findings demonstrate that down-regulation of splicing factor, such as SRSF3, to alter cell cycle progression, cell death and invasion is a potential target for the drug repositioning of cardiac glycosides.

Topics: Alternative Splicing; Animals; Apoptosis; Blotting, Western; Cadherins; Cardiotonic Agents; Cell Line; Cell Line, Tumor; Digoxin; Dose-Response Relationship, Drug; Epithelial-Mesenchymal Transition; G2 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Neoplasms; Protein Isoforms; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Proteins; Serine-Arginine Splicing Factors; Signal Transduction; Snail Family Transcription Factors; Transcription Factors; Tumor Suppressor Protein p53

Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their receptor, Na,K-ATPase, through which, they inhibit Na+ and K+ ion transport and activate of several intracellular signaling pathways. In this study, we added a styrene group to the lactone ring of the cardiotonic steroid digoxin, to obtain 21-benzylidene digoxin (21-BD), and investigated the effects of this synthetic cardiotonic steroid in different cell models. Molecular modeling indicates that 21-BD binds to its target Na,K-ATPase with low affinity, adopting a different pharmacophoric conformation when bound to its receptor than digoxin. Accordingly, 21-DB, at relatively high µM amounts inhibits the activity of Na,K-ATPase α1, but not α2 and α3 isoforms. In addition, 21-BD targets other proteins outside the Na,K-ATPase, inhibiting the multidrug exporter Pdr5p. When used on whole cells at low µM concentrations, 21-BD produces several effects, including: 1) up-regulation of Na,K-ATPase expression and activity in HeLa and RKO cancer cells, which is not found for digoxin, 2) cell specific changes in cell viability, reducing it in HeLa and RKO cancer cells, but increasing it in normal epithelial MDCK cells, which is different from the response to digoxin, and 3) changes in cell-cell interaction, altering the molecular composition of tight junctions and elevating transepithelial electrical resistance of MDCK monolayers, an effect previously found for ouabain. These results indicate that modification of the lactone ring of digoxin provides new properties to the compound, and shows that the structural change introduced could be used for the design of cardiotonic steroid with novel functions.

Topics: Animals; Apoptosis; Cardenolides; Cell Line, Tumor; Digoxin; Enzyme Activation; Epithelial Cells; Humans; Mice; Models, Molecular; Molecular Conformation; Neoplasms; Rats; Sodium-Potassium-Exchanging ATPase; Tight Junctions

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.

Topics: Animals; Anthracyclines; Antineoplastic Agents; Biosensing Techniques; Cardiac Glycosides; Cell Line, Tumor; Digoxin; Humans; Mice; Neoplasms; Organoplatinum Compounds; Oxaliplatin

Topics: Animals; Antineoplastic Agents; Digoxin; Enzyme Inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms

Topics: Animals; Cell Survival; Digoxin; Humans; Hypoxia-Inducible Factor 1; Neoplasms

Topics: Angiogenesis Inhibitors; Animals; Anthracyclines; Antibiotics, Antineoplastic; Breast Neoplasms; Cell Hypoxia; Digoxin; Female; Humans; Hypoxia-Inducible Factor 1; Lung Neoplasms; Male; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Transplantation, Heterologous

Review of the literature suggests that misdiagnosis of terminal illness is infrequent. In the first 6 months of the recently established Edmonton Regional Palliative Care Program, two of 330 referrals proved to be in the category of erroneous diagnosis of terminal disease. These two cases are reported, along with discussion of aspects of the time-honored usefulness of careful history and physical examination. This experience highlights the importance of assessment, investigation, and aggressive therapy, even in "terminal" patients, including those in the geriatric population.

Topics: Acute Kidney Injury; Adaptation, Psychological; Aged; Aged, 80 and over; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Tricyclic; Chest Pain; Coronary Disease; Depression; Diagnosis, Differential; Diagnostic Errors; Digoxin; Female; Geriatrics; Grief; Humans; Morphine; Neoplasms; Nortriptyline; Palliative Care; Stomach Ulcer; Terminally Ill; Weight Loss

Topics: Animals; Antibodies, Monoclonal; Binding, Competitive; Biomarkers, Tumor; Biosensing Techniques; Digoxin; Ferritins; Fiber Optic Technology; Fluorescent Dyes; Humans; Immunoassay; Molecular Weight; Neoplasms; Optical Fibers; Rabbits

Twenty-one patients with various advanced neoplasms were treated with 60 to 75 mg/m2 of doxorubicin every 3 to 4 weeks and monitored by ECG and systolic time intervals (PEP/LVET) with the aim to establish whether a pretreatment with beta-methyldigoxin, administered intermittently, could prevent doxorubicin-induced cardiotoxicity. It was found that until patients received digitalis pretreatment the PEP/LVET ratio did not change significantly from mean basal values even after the highest cumulative dosages of doxorubicin. However, after interruption of the therapy with both drugs, PEP/LVET increased reaching a value not significantly different from that observed in a comparable group of patients treated only with doxorubicin. Moreover, of 9 patients who reached the cumulative limiting dose, 2 developed congestive heart failure. These results question the possibility that digitalis administered according to an intermittent treatment scheme may prevent doxorubicin cardiomyopathy.

Topics: Adolescent; Adult; Aged; Child; Digoxin; Dose-Response Relationship, Drug; Doxorubicin; Electrocardiography; Female; Heart; Heart Function Tests; Humans; Male; Medigoxin; Middle Aged; Neoplasms; Systole

Topics: Adult; Cardiomegaly; Digoxin; Doxorubicin; Electrocardiography; Female; Heart; Heart Diseases; Heart Failure; Heart Function Tests; Heart Ventricles; Humans; Lymphoma; Male; Middle Aged; Multiple Myeloma; Neoplasms; Prospective Studies

Topics: Chlorambucil; Chloramphenicol; Cytomegalovirus Infections; Diagnosis, Differential; Digoxin; Electrons; Hodgkin Disease; Humans; Hydrocortisone; Infant; Lung Diseases; Mechlorethamine; Microscopy; Microscopy, Electron; Neoplasms; Pathology; Penicillins; Plasma Cells; Pneumonia; Pneumonia, Pneumocystis; Streptomycin

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Digoxin; Diuretics; Humans; Lung Neoplasms; Neoplasm Regression, Spontaneous; Neoplasms; Radiography, Thoracic; Rest