digoxin and Carcinoma--Non-Small-Cell-Lung

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

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

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

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

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