digoxin and Lung-Neoplasms

Capmatinib, an orally bioavailable, highly potent and selective MET inhibitor, was recently approved to treat adult patients with metastatic nonsmall cell lung cancer with METex14 skipping mutations. The study investigated the effect of capmatinib on the pharmacokinetics of a single oral dose of digoxin and rosuvastatin in patients with MET-dysregulated advanced solid tumours.. This was a multicentre, open-label, single-sequence study. An oral drug cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin was administered to adult patients with MET-dysregulated advanced solid tumours on Day 1, and then on Day 22 with capmatinib. Between Days 11 and 32, capmatinib 400 mg was administered twice daily to ensure the attainment of steady state for drug-drug interaction assessment. Pharmacokinetics of cocktail drugs and safety of capmatinib were evaluated.. Thirty-two patients were enrolled. Compared to digoxin alone, the geometric mean ratios (90% confidence interval) of area under the concentration-time curve from time zero to infinity and maximum concentration for digoxin plus capmatinib were 1.47 (1.28, 1.68) and 1.74 (1.43, 2.13), respectively. Compared to rosuvastatin alone, the geometric mean ratios (90% confidence interval) of area under the curve to infinity and maximum concentration for rosuvastatin plus capmatinib were 2.08 (1.56, 2.76) and 3.04 (2.36, 3.92), respectively. Most frequent adverse events (≥25% for all grades) were nausea, asthenia, constipation, vomiting, peripheral oedema and pyrexia. Most frequent Grade 3/4 adverse events (≥5%) were anaemia, pulmonary embolism, asthenia, dyspnoea, nausea and vomiting.. This study demonstrated that capmatinib is an inhibitor of P-gp and BCRP transporters, with clinically relevant drug-drug interaction potential. Capmatinib was well-tolerated and no unexpected safety concerns were observed.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Benzamides; Carcinoma, Non-Small-Cell Lung; Digoxin; Drug Interactions; Humans; Imidazoles; Lung Neoplasms; Neoplasm Proteins; Pharmaceutical Preparations; Rosuvastatin Calcium; Triazines

This prospective study was designed to determine whether diltiazem is superior to digoxin for the prophylaxis of supraventricular dysrhythmias (SVD) after pneumonectomy or extrapleural pneumonectomy (EPP) and to assess the influence of these drugs on perioperative cardiac function.. Seventy consecutive patients without previous SVD were randomly allocated immediately after pneumonectomy or EPP to receive diltiazem (n = 35) or digoxin (n = 35). Diltiazem-treated patients received a slow intravenous loading dose of 20 mg, followed by 10 mg intravenously every 4 hours for 24 to 36 hours, then 180 to 240 mg orally daily for 1 month. Digoxin-treated patients received a 1-mg intravenous loading in the first 24 to 36 hours, then 0.125 to 0.25 mg orally daily for 1 month. A concurrent prospective cohort of 40 patients without previous SVD, who did not participate in the study and underwent pneumonectomy or EPP without prophylaxis, served as a comparison group for SVD occurrence. Serial Doppler echocardiograms were performed to assess cardiac function and all patients were continuously monitored with Holter recorders for 3 days. Data were analyzed by intent-to-treat.. In patients undergoing standard or intrapericardial pneumonectomy, diltiazem prevented the overall incidence of postoperative SVD when compared with digoxin, 0 of 21 patients versus 8 of 25 patients, respectively, p < 0.005. When EPP patients were included in the analysis, diltiazem decreased the incidence of all SVD from 11 of 35 patients (31%) to 5 of 35 patients (14%) when compared with digoxin, p = 0.09. Digoxin-treated patients had a similar incidence of all SVD (31%) as concurrent controls (11 of 40 patients [28%]). The two treated groups did not differ in right or left atrial size, left ventricular ejection fraction, or right heart pressure. When all patients were combined, those in whom SVD developed were significantly older (65 +/- 12 years versus 55 +/- 11 years, p = 0.004) and had a longer median hospital stay (9 versus 6 days, p = 0.03), when compared with those in whom SVD did not develop, respectively. The subset of patients undergoing EPP had a greater incidence of atrial fibrillation and electrocardiographic changes suggestive of postoperative pericarditis than all other pneumonectomy patients.. Diltiazem was both safe and more effective than digoxin in reducing the overall incidence of SVD after standard or intrapericardial pneumonectomy. Digoxin therapy had no effect on the incidence of postoperative SVD and is not recommended for prophylaxis of SVD. Dysrhythmias after pneumonectomy or EPP occur in older patients and are associated with a greater length of hospital stay.

Topics: Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Digoxin; Diltiazem; Echocardiography, Doppler; Female; Heart; Humans; Lung Neoplasms; Male; Middle Aged; Pleural Neoplasms; Pneumonectomy; Prospective Studies; Treatment Outcome; Ventricular Pressure

Lung cancer remains the leading cause of cancer mortality because of its metastatic potential and high malignancy. The discovery of new applications for old drugs is a shortcut for cancer therapy. We recently investigated the antitumor effect of digoxin, a well-established drug for treating heart failure, against nonsmall cell lung cancer A549 and H1299 cells. Digoxin inhibited the proliferation and colony-forming ability of the two cell lines and arrested the cell cycle at the G0/G1 phase in A549 cells and the G2/M phase in H1299 cells. Mitochondria-mediated apoptosis was induced in A549 cells but not in H1299 cells after treatment with digoxin. Moreover, digoxin inhibited the migration, invasion, adhesion and epithelial-mesenchymal transition of A549 and H1299 cells. Autophagy was induced in both cell lines after treatment with digoxin, with an increase in autophagosome foci. In addition, digoxin inhibited the phosphorylation of Akt, mTOR and p70S6K, signaling molecules of the PI3K/Akt pathway that are known to be involved in tumor cell survival, proliferation, metastasis and autophagy. Our findings suggest that digoxin has the potential to be used for therapy for human nonsmall cell lung cancer, but further evidence is required.

Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Autophagy; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Movement; Cell Proliferation; Digoxin; Epithelial-Mesenchymal Transition; Humans; Lung Neoplasms; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction

Although STK11 (LKB1) mutation is a major mediator of lung cancer progression, targeted therapy has not been implemented due to STK11 mutations being loss-of-function. Here, we report that targeting the Na(+)/K(+)-ATPase (ATP1A1) is synthetic lethal with STK11 mutations in lung cancer. The cardiac glycosides (CGs) digoxin, digitoxin and ouabain, which directly inhibit ATP1A1 function, exhibited selective anticancer effects on STK11 mutant lung cancer cell lines. Restoring STK11 function reduced the efficacy of CGs. Clinically relevant doses of digoxin decreased the growth of STK11 mutant xenografts compared to wild type STK11 xenografts. Increased cellular stress was associated with the STK11-specific efficacy of CGs. Inhibiting ROS production attenuated the efficacy of CGs, and STK11-AMPK signaling was important in overcoming the stress induced by CGs. Taken together, these results show that STK11 mutation is a novel biomarker for responsiveness to CGs. Inhibition of ATP1A1 using CGs warrants exploration as a targeted therapy for STK11 mutant lung cancer.

Topics: A549 Cells; AMP-Activated Protein Kinase Kinases; Animals; Cardiac Glycosides; Cardiotonic Agents; Cell Line, Tumor; Digitoxin; Digoxin; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice, Nude; Mutation; Ouabain; Protein Serine-Threonine Kinases; RNA Interference; Xenograft Model Antitumor Assays

Non-small cell lung cancer is the predominant type of lung cancer, resulting in high mortality worldwide. Digoxin, a cardiac glycoside, has recently been suggested to be a novel chemotherapeutic agent. Src is an oncogene that plays an important role in cancer progression and is therefore a potential target for cancer therapy. Here, we investigated whether digoxin could suppress lung cancer progression through the inhibition of Src activity. The effects of digoxin on lung cancer cell functions were investigated using colony formation, migration and invasion assays. Western blotting and qPCR assays were used to analyze the mRNA and protein expression levels of Src and its downstream proteins, and a cell viability assay was used to measure cellular cytotoxicity effects. The results of the cell function assays revealed that digoxin inhibited the proliferation, invasion, migration, and colony formation of A549 lung cancer cells. Similar effects of digoxin were also observed in other lung cancer cell lines. Furthermore, we found that digoxin significantly suppressed Src activity and its protein expression in a dose- and time-dependent manner as well as reduced EGFR and STAT3 activity. Our data suggest that digoxin is a potential anticancer agent that may suppress lung cancer progression through inhibiting Src and the activity of related proteins.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Death; Cell Line, Tumor; Cell Movement; Cell Survival; Digoxin; Enzyme Activation; ErbB Receptors; Focal Adhesion Protein-Tyrosine Kinases; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Models, Biological; Neoplasm Invasiveness; Phosphorylation; RNA, Messenger; Signal Transduction; src-Family Kinases; STAT3 Transcription Factor; Tumor Stem Cell Assay

Lung cancer causes over one million deaths every year worldwide. However, prevention and treatment methods for this serious disease are limited. The identification of new chemicals related to lung cancer may aid in disease prevention and the design of more effective treatments. This study employed a weighted network, constructed using chemical-chemical interaction information, to identify new chemicals related to two types of lung cancer: non-small lung cancer and small-cell lung cancer. Then, a randomization test as well as chemical-chemical interaction and chemical structure information were utilized to make further selections. A final analysis of these new chemicals in the context of the current literature indicates that several chemicals are strongly linked to lung cancer.

Topics: Animals; Antineoplastic Agents; Arsenicals; Berberine; Carcinogenesis; Carcinoma, Non-Small-Cell Lung; Colchicine; Daunorubicin; Digoxin; Drug Discovery; Humans; Lung; Lung Neoplasms; Ouabain; Prednisone; Small Cell Lung Carcinoma; Tretinoin

The presence of bacteria within the pocket epithelium and underlying connective tissue in gingival biopsies from patients with periodontitis has been reported using various methods, including electron microscopy, immunohistochemistry or immunofluorescence using bacteria-specific antibodies, and fluorescent in situ hybridization (FISH) using a fluorescence-labeled oligonucleotide probe. Nevertheless, these methods are not widely used due to technical limitation or difficulties. Here a method to localize bacteria within paraffin-embedded tissues using DIG-labeled DNA probes has been introduced. The paraffin-embedded tissues are the most common form of biopsy tissues available from pathology banks. Bacteria can be detected either in a species-specific or universal manner. Bacterial signals are detected as either discrete forms (coccus, rod, fusiform, and hairy form) of bacteria or dispersed forms. The technique allows other histological information to be obtained: the epithelia, connective tissue, inflammatory infiltrates, and blood vessels are well distinguished. This method can be used to study the role of bacteria in various diseases, such as periodontitis, cancers, and inflammatory immune diseases.

Topics: Animals; Bacteria; Digoxin; DNA Probes; Fluorescent Dyes; Helicobacter pylori; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lichen Planus; Lung Neoplasms; Mice; Mice, Inbred BALB C; Paraffin Embedding; Porphyromonas gingivalis; RNA, Ribosomal, 16S

Digoxin, an inhibitor of Na+/K+ ATPase, has been used in the treatment of heart-related diseases (such as congestive heart failure and atrial arrhythmia) for decades. Recently, it was reported that digoxin is also an effective HIF-1α inhibitor. We investigated whether digoxin could suppress tumor cell growth through HIF-1α in non-small cell lung cancer cells (A549 cells) under hypoxic conditions. An MTT assay was used to measure cell viability. RT-PCR and western blotting were performed to analyze the mRNA and protein expression of VEGF, NDRG1, and HIF-1α. HIF-1α nuclear translocation was then determined by EMSA. Digoxin was found to inhibit the proliferation of A549 cells under hypoxic conditions. Our results showed that hypoxia led to the upregulation of VEGF, NDRG1, and HIF-1α both at the mRNA and protein levels. We also found that the hypoxia-induced overexpression of VEGF, NDRG1, and HIF-1α was suppressed by digoxin in a concentration-dependent manner. As expected, our EMSA results demonstrated that under hypoxic conditions HIF-1α nuclear translocation was also markedly reduced by digoxin in a concentration-dependent manner. Our results suggest that digoxin downregulated hypoxia-induced overexpression of VEGF and NDRG1 at the transcriptional level probably through the inhibition of HIF-1α synthesis in A549 cells.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Cell Cycle Proteins; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Digoxin; DNA, Neoplasm; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; RNA, Messenger; Vascular Endothelial Growth Factor A

Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through increased expression of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins, enzymes that remodel collagen at the metastatic site and recruit bone marrow-derived cells (BMDCs) to the metastatic niche. We investigated the effect of two chemically and mechanistically distinct HIF inhibitors, digoxin and acriflavine, on breast cancer metastatic niche formation. Both drugs blocked the hypoxia-induced expression of LOX and LOXL proteins, collagen cross-linking, CD11b⁺ BMDC recruitment, and lung metastasis in an orthotopic breast cancer model. Patients with HIF-1 α-overexpressing breast cancers are at increased risk of metastasis and mortality and our results suggest that such patients may benefit from aggressive therapy that includes a HIF inhibitor.

Topics: Acriflavine; Amino Acid Oxidoreductases; Animals; Bone Marrow Cells; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Digoxin; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1; Lung Neoplasms; Mice; Mice, SCID; Neoplasm Metastasis; Protein-Lysine 6-Oxidase; Xenograft Model Antitumor Assays

Na(+)/K(+)-ATPase targeted cancer therapy has attracted increasing interests of oncologists in lung cancer field. Although multiple anti-cancer mechanisms of cardiac glycosides as Na(+)/K(+)-ATPase inhibitors are revealed, the role of autophagy and related molecular signaling pathway for the class of compounds in human non-small cell lung cancer (NSCLC) cells has not been systematically examined. We herein investigated the anti-cancer effects of two representative cardiac glycosides, digoxin and ouabain, in A549 and H460 cell lines. Both agents caused significant growth inhibition at nanomolar level. The cardiac glycosides were found to induce moderate G(2)/M arrest but not apoptosis at IC(50) level in the NSCLC cell lines. Moreover, autophagy was markedly induced by both agents, as evidenced by the time- and dose-dependent increase of LC3-II, up-regulation of Atg5 and Beclin1, as well as by the observations through acridine orange staining, transmission electron microscopy and quantification of GFP-LC3 fluorescence. Importantly, AMP-activated protein kinase (AMPK) pathway was activated, resulting in mammalian target of rapamycin (mTOR) deactivation during autophagy induction. Moreover, extracellular-signal-regulated kinase 1/2 (ERK1/2) activation was simultaneously found to be involved in the autophagy regulation. Co-treatment with respective inhibitors or siRNAs could either block the autophagic phenotypes and signals, or significantly increase the cellular viability, indicating the drugs-induced autophagy plays tumor-suppressing role. This work provides first evidence showing that the cardiac glycosides induce autophagy in human NSCLC cells through regulation of both mTOR and ERK1/2 signaling pathways. The autophagy may at least partially account for the growth inhibitory effects of the compounds in human NSCLC cells.

Topics: AMP-Activated Protein Kinases; Androstadienes; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Protein 5; Beclin-1; Biomarkers; Carcinoma, Non-Small-Cell Lung; Cardiac Glycosides; Cell Line, Tumor; Digoxin; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; G2 Phase Cell Cycle Checkpoints; Gene Knockdown Techniques; Humans; Inhibitory Concentration 50; Lung Neoplasms; MAP Kinase Signaling System; Membrane Proteins; Microtubule-Associated Proteins; Mitosis; Ouabain; Signal Transduction; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Vacuoles; Wortmannin

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

This study investigated the association of COPD and postoperative cardiac arrhythmias, specifically supraventricular tachycardia (SVT), as well as mortality in patients undergoing pulmonary resection for non-small cell lung cancer (NSCLC).. A retrospective chart review of 244 patients who had undergone lung resection for NSCLC at Indiana University Hospital between 1992 and 1997 was undertaken. COPD, which was defined as an FEV(1) of < or = 70% predicted and an FEV(1)/FVC ratio of < or = 70% based on the results of a preoperative pulmonary function test (PFT), was diagnosed in 78 of the 244 patients (COPD group). In the remaining 166 patients, the results of preoperative PFTs did not meet these criteria (non-COPD group). Both groups were otherwise well-matched with respect to multiple variables, including age, comorbid conditions, extent of pulmonary resection, and final pathologic stage. The incidence of cardiac arrhythmias and operative mortality were compared between the two groups using univariate and multivariate analysis.. Seventy-six patients (31.9%) experienced new onsets of postoperative SVT, with 58 of these patients (76.3%) demonstrating atrial fibrillation. The COPD group had a 58.7% incidence of SVT (n = 44) compared to a 27.0% incidence (n = 44) in the non-COPD group (p < 0.0 0 1). Moreover, following initial digoxin therapy, the COPD group required more second-line antiarrhythmic therapy than did the non-COPD group (66.7% vs 37.8%, respectively; p = 0.0 03). Overall, there were 16 operative deaths (6.6%), and the mortality rate was significantly higher in the COPD group (14.1%) than in the non-COPD group (3.0%; p = 0.0 04). Patients who developed SVT had a significantly longer hospital course than did patients who did not (p < 0.0001). Thirteen of the 16 patients who died experienced SVT; however, SVT was not an independent risk factor for death. Finally, of the 19 variables evaluated, major resection (ie, pneumonectomy and bilobectomy) and COPD were identified as independent risk factors for the development of cardiac arrhythmias (p = 0.0 033 and p = 0.0 009, respectively).. Patients with COPD, as defined by the results of preoperative PFTs, are at significantly higher risk for SVT, and in particular SVT refractory to digoxin, following pulmonary resection for NSCLC. Although SVT was not an independent risk factor for death, a significantly longer hospitalization was observed.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Carcinoma, Non-Small-Cell Lung; Cause of Death; Digoxin; Female; Forced Expiratory Volume; Hospital Mortality; Humans; Lung Neoplasms; Male; Middle Aged; Pneumonectomy; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Risk Factors; Survival Rate; Tachycardia, Supraventricular; Vital Capacity

To further define the chemical structure of human endogenous digoxinlike immunoreactive factors (DLIF) we used human pleural effusions as a source of the substance. Digoxinlike immunoreactive factor activity was detected by radioimmunoassay in the pleural fluid of each of four patients; average concentration was 0.35 ng/mL. The chemical profile of DLIF was determined by initial extraction and concentration of DLIF by ion exchange chromatography followed by reverse phase-high-pressure liquid chromatography (RP-HPLC) separation and purification. Using high-pressure liquid chromatography cochromatography of DLIF, together with several radioactively marked glycosides, we observed a single peak of DLIF activity that was chromatographically identical to digoxin. The present study further supports the recent finding that DLIF is related structurally to the cardiac glycosides, and for the first time it has been proven that DLIF is present in pleural fluids.

Topics: Cardenolides; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Digoxin; Female; Humans; Lung Neoplasms; Male; Pleural Effusion; Renal Insufficiency; Saponins

A total of 238 patients undergoing resection of lung cancer were studied for the occurrence of postoperative arrhythmia. Transient arrhythmia was observed in 43 of them (18.1%). Ninety-one percent of 43 patients developed atrial fibrillation (Af), even though no arrhythmia was noted on ECG in any patient preoperatively. Cardiac dysrhythmia occurred 5.2 +/- 3.8 days after operation and lasted for 1.3 +/- 0.9 days (mean +/- SD). There was a significant difference (p less than 0.05) in the incidence of postoperative arrhythmia between the male group (39/188 = 21%) and the female group (4/50 = 8%), however the cause of a difference is unknown. The incidence was higher in patients undergoing pneumonectomy than in those undergoing lobectomy. Patients, who suffered from postoperative arrhythmia, has significantly low values on pulmonary function test (FEV1.0% = 68.7%) preoperatively. The increased cardiac load after the reduction of the pulmonary vascular bed was regarded as the most important factor of arrhythmia. Prophylactic administration of digoxin was performed in another 61 male patients after resection of lung cancer. And it was found to be effective in decreasing the incidence of postoperative atrial fibrillation (5/61 = 8%).

Topics: Adult; Aged; Arrhythmias, Cardiac; Carcinoma, Bronchogenic; Digoxin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pneumonectomy

Topics: Adult; Aged; Digitalis Glycosides; Digoxin; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Humans; Lung Neoplasms; Male; Medigoxin; Middle Aged; Premedication; Spironolactone

Topics: Age Factors; Aged; Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Flutter; Digitoxin; Digoxin; Female; Humans; Lung; Lung Neoplasms; Male; Middle Aged; Postoperative Complications

Topics: Angiomatosis; Cholesterol; Chylomicrons; Chylothorax; Chylous Ascites; Digoxin; Diuretics; Drug Therapy; Exudates and Transudates; Geriatrics; Glycerides; Heart Failure; Humans; Lipids; Lung Neoplasms; Nephrotic Syndrome; Prednisone; Tritium

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