Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/ß-catenin/c-Myc signaling pathway in human gastric cancer cell.

Gastric cancer is the third common cause of cancer mortality in the world with poor prognosis and high recurrence due to lack of effective medicines. Our studies revealed that lanatoside C, a FDA-approved cardiac glycoside, had an anti-proliferation effect on different human cancer cell lines (MKN-45; SGC-7901; HN4; MCF-7; HepG2) and gastric cell lines MKN-45 and SGC-7901 were the most sensitive cell lines to lanatoside C. MKN-45 cells treated with lanatoside C showed cell cycle arrest at G2/M phase and inhibition of cell migration. Meanwhile, upregulation of cleaved caspase-9 and cleaved PARP and downregulation of Bcl-xl were accompanied with the loss of mitochondrial membrane potential (MMP) and induction of intracellular reactive oxygen species (ROS). Lanatoside C inhibited Wnt/ß-catenin signaling with downregulation of c-Myc, while overexpression of c-Myc reversed the anti-tumor effect of lanatoside C, confirming that c-Myc is a key drug target of lanatoside C. Furthermore, we discovered that lanatoside C prompted c-Myc degradation in proteasome-ubiquitin pathway with attenuating the binding of USP28 to c-Myc. These findings indicate that lanatoside C targeted c-Myc ubiquitination to inhibit MKN-45 proliferation and support the potential value of lanatoside C as a chemotherapeutic candidate.

Cedilanid inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy.

PURPOSE: This study investigated the effect of cedilanid on retinal neovascularization in a mouse model of oxygen-induced retinopathy. METHODS: Seven-day-old C57BL/6 mice were exposed to 75% ± 1% oxygen for 5 days and were then returned to room air to induce retinal neovascularization. Cedilanid (0.025-0.2 µg) was intravitreally injected into the left eye of each mouse on postnatal day 12 (P12) and P15. PBS was intravitreally injected into the right eye as a control. Retinal neovascularization was evaluated with isolectin GS-IB4 staining of the retinal blood vessels. The function of reestablishment blood vessels was evaluated with angiography with the injection of fluorescein isothiocyanate (FITC)-dextran followed by isolectin GS-IB4 staining. Real time (RT)-PCR and western blot were used to examine the mRNA and protein expression of hypoxia inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF), respectively. RESULTS: Retinal neovascular areas and obliterative areas were statistically significantly smaller in the eyes injected with cedilanid (0.05 µg, 0.1 µg, and 0.2 µg) compared with the control eyes. The inhibitory effect of cedilanid was observed in a dose-dependent manner. In addition, the retinal neovascular areas and the obliterative areas in the eyes injected with 0.2 µg cedilanid on P12 were statistically significantly smaller than those in the eyes injected with the same dose of cedilanid on P15. Cedilanid promoted the circulative function of reestablished blood vessels in the obliterative areas. Cedilanid inhibited the expression of HIF-1α and VEGF in mice treated with hyperoxia. CONCLUSIONS: Cedilanid inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy. Early treatment with cedilanid produces better inhibition of retinal neovascularization. Cedilanid may be a potential treatment of neovascular diseases.

Protein-protein interaction network analysis in chronic obstructive pulmonary disease.

BACKGROUND: The aim of this study was to investigate the gene expression profile of chronic obstructive pulmonary disease (COPD) patients and non-COPD patients. METHODS: Microarray raw data (GSE29133) was downloaded from Gene Expression Omnibus, including three COPD samples and three normal controls. Gene expression profiling was performed using Affymetrix human genome u133 plus 2.0 GeneChip. Differentially expressed genes were identified by Student's t test and genes with p < 0.05 were considered significantly changed. Up- and downregulated genes were submitted to the molecular signatures database (MSigDB) to search for a possible association with other previously published gene expression signatures. Furthermore, we constructed a COPD protein-protein interaction (PPI) network and used the connectivity map (cMap) to query for potential drugs for COPD. RESULTS: A total of 680 upregulated genes and 530 downregulated genes in COPD were identified. The MSigDB investigation found that upregulated genes were highly similar to gene signatures that respond to interferon and downregulated genes were similar to erythroid progenitor cells from fetal livers of E13.5 embryos with KLF1 knocked out. A PPI network consisting of 814 gene/proteins and 2,613 interactions was identified by Search Tool for the Retrieval of Interacting Genes. The cMap predicted helveticoside, disulfiram, and lanatoside C as the top three possible drugs that could perhaps treat COPD. CONCLUSION: Comprehensive analysis of the gene expression profile for COPD versus control reveals helveticoside, disulfiram, and lanatoside C as potential molecular targets in COPD. This evidence provides a new breakthrough in the medical treatment of patients with COPD.

Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand and induces an alternative cell death pathway.

Human glioblastoma (GBM) cells are notorious for their resistance to apoptosis-inducing therapeutics. We have identified lanatoside C as a sensitizer of GBM cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death partly by upregulation of the death receptor 5. We show that lanatoside C sensitizes GBM cells to TRAIL-induced apoptosis in a GBM xenograft model in vivo. Lanatoside C on its own serves as a therapeutic agent against GBM by activating a caspase-independent cell death pathway. Cells treated with lanatoside C showed necrotic cell morphology with absence of caspase activation, low mitochondrial membrane potential, and early intracellular ATP depletion. In conclusion, lanatoside C sensitizes GBM cells to TRAIL-induced cell death and mitigates apoptosis resistance of glioblastoma cells by inducing an alternative cell death pathway. To our knowledge, this is one of the first examples of use of caspase-independent cell death inducers to trigger tumor regression in vivo. Activation of such mechanism may be a useful strategy to counter resistance of cancer cells to apoptosis.

Drug therapy of paroxysmal atrial fibrillation in the elderly over 75 years old.

OBJECTIVE: To investigate the effectiveness and safety of various agents on paroxysmal atrial fibrillation in the elderly over 75 years old. METHODS: Totally 264 in-patients (75-91 years old, 185 males and 79 females) with atrial fibrillation history of less than 7 days were enrolled in this study. A total of 611 atrial fibrillation episodes were recorded, but 130 episodes (22.3%) of atrial fibrillation were auto-converted to sinus rhythm. The rest 481 episodes of atrial fibrillation were divided into six groups based on the drug used. RESULTS: The cardioversion ratio of atrial fibrillation were 9.5%, 46.9%, 71.7%, 55.9%, 32.7%, and 73.6% in control, cedilanid, amiodarone, propafenone, verapamil, and quinidine groups, respectively. Ventricular rate control were 5.4%, 83.6%, 84.9%, 77.9%, 78.8%, and 11.3% in those groups, respectively. The total effective rates of amiodarone and cedilanid groups were the highest. When the ventricular rate was controlled to below 90 bpm, the patients would almost complain of no discomfort. No severe side-effect was observed in each group. CONCLUSION: Amiodarone and cedilanid may be the proper drugs for the treatment of paroxysmal atrial fibrillation in the elderly. The above antiarrhythmics in each therapeutic group were relatively safe and effective.

[Cardiac glycosides in complex treatment of patients with heart failure and supraventricular arrhythmias].

The authors of the article studied potential of various drug combinations (atenolol + enalapril + indapamide, and celanid + enalapril + indapamide) in complex treatment of patients with heart failure (HF) and supraventricular arrhythmias. The subjects were 106 patients, of whom 74 had coronary heart disease, of whom 51 had old myocardial infarction, and 18 had undergone coronary artery bypass grafting. Dilatation cardiomyopathy was found in 8, aortomitral valvular disease--in 18, and combined mitral valvular disease--in 6 patients. 36 subjects had permanent atrial fibrillation, 48--a paroxysmal form of ciliary arrhythmia, 22--paroxysms of atrial tachycardia. NYHA functional class (FC) II HF was diagnosed in 64 patients, NYHA FC III HF--in 42 patients. According to what treatment regimen was applied, the patients were divided into two groups, comparable in the main clinical and functional characteristics. Two-month therapy resulted in improvement of hemodynamics, increase of activity tolerance and improvement of life quality in both groups. The combination celanide + enalapril + indapamide in individual doses was effective in FC II-III HF with supraventricular arrhythmias. The cost of treatment with celanid is lower.

Digitalis restores the forearm sympathetic response to cardiopulmonary receptor unloading in hypertensive patients with left ventricular hypertrophy.

OBJECTIVE: To investigate whether the impaired reflex response to cardiopulmonary baroreceptor unloading in hypertensive patients with left ventricular hypertrophy can be promptly improved by a pharmacological challenge. For this purpose we studied the effects of acute digitalis administration on cardiopulmonary baroreflex, evaluated by forearm noradrenaline spillover. METHODS: Eleven hypertensives with left ventricular hypertrophy and 10 age- and sex-matched normotensives underwent the application of -5 and -10 mmHg lower-body negative pressure (LBNP) before and after the administration of digitalis. Forearm noradrenaline spillover, measured using a tracer technique, was used to estimate the reflex sympathetic response. RESULTS: Under control conditions LBNP evoked a similar fall in right atrial pressure in the two study groups. In the normotensives there was a significant increase in forearm noradrenaline spillover. In the hypertensives no significant changes in forearm noradrenaline spillover were found. Intravenous administration of 0.02 mg/kg lanatoside C was associated with an increase in systolic blood pressure and a reduction in forearm noradrenaline spillover in both groups. In the normotensives the percentage change in forearm noradrenaline spillover induced by LBNP increased significantly in response to digitalis administration. However, digitalis restored the response of forearm noradrenaline spillover to LBNP in the hypertensives, so that no significant difference in this response was detected between the two study groups. Digitalis did not modify the effects of LBNP on cardiac pressures in either group. CONCLUSIONS: The present results demonstrate that administration of lanatoside C restores the response of forearm noradrenaline spillover to cardiopulmonary baroreceptor unloading in hypertensive patients with left ventricular hypertrophy. This indicates that the impairment of cardiopulmonary baroreflexes in these patients can be reversed by acute pharmacological treatment. Therefore, impairment of this reflex response seems to be related to functional rather than to structural abnormalities of the hypertrophied ventricle.

[A study on the hemodynamic effect of cedilanid in the treatment of acute myocardial infarction].

For long time, there has been controversy on the use of digitalis in acute myocardial infarction (AMI). Hemodynamic studies before and after the use of cedilanid, simple QRS scoring, changes on the score of AMI and cardiac arrhythmia were analysed on 24 cases of AMI. Results of the pre- and post-medication values were improved as following: (1) Cardiac index (CI) were 2.34 +/- 0.2 and 3.21 +/- 0.26L/min/m2 two hours after medication (P < 0.05). (2) Left ventricular stroke work index (LVSWI) were 31.2 +/- 3.4 and 40.1 +/- 2.2 g-m/beat/m2 two hours after medication (P < 0.01). (3) Pulmonary capillary wedge pressure (PCWP) were 19.5 +/- 2.4 and 13.2 +/- 2.1 mmHg two hours after medication (P < 0.01). (4) Myocardial oxygen consumption triple index (TI) were 182000 +/- 14000 and 142000 +/- 12000 two hours after medication (P < 0.01). (5) There was no change or with only trivial aberration on systemic vascular resistance (SVR) and perfusion pressure of the coronary arteries (CCP). (6) Simple QRS scoring on electrocardiogram resulted that the size of infarcted areas were 4.02 +/- 0.3 points before and 3.01 +/- 0.23 points after the medication (P < 0.01), there was neither ventricular premature beats (VPB) nor increase of any other serious cardiac arrhythmias in the electrocardiogram care and record in 72 hours. From the hemodynamic studies, the beneficial effect of cedilanid is greater than its adverse effect. It is concluded that digitalis can be safely and effectively used in the treatment of AMI.

Contribution of clinical pharmacology to a rational use of cardiac glycosides in Czechoslovakia.

In Czechoslovakia, drug utilization studies showed that oral forms of digoxin and lanatoside C are traditionally the most prescribed cardiac glycosides. Our study of the relative bioavailability of the oral form of lanatoside C revealed that the drug has a low and irregular bioavailability making use of this frequently prescribed drug non-rational. The above data definitely contributed to a sharp decrease in the use of the oral form of lanatoside C in our country, which is in agreement with consumption trends in other European countries. However, the use of only drug forms with a good bioavailability is one aspect of new approaches applied in pharmacotherapy with cardiac glycosides resulting in gradual decrease of their consumption as a pharmacological group. Clinical pharmacological evaluation of individual drug forms and postgraduate education in clinical pharmacology of cardiac glycosides contribute significantly--apart from other regulatory measures--to a more rational use of cardiac glycosides in Czechoslovakia.

[Curbing of arrhythmias under outpatient polyclinic conditions]. / Prekusvane na ritumni narusheniia pri ambulatorno-poliklinichni usloviia.

The material has been collected in the course of two years and covers 48 cases with paroxysms of supraventricular paroxysmal tachycardia (28), auricular fibrillation (4) ventricular tachycardia (2), group and polytopic ventricular extrasystoles (14), organic cardiac diseases (30) and 18--inorganic heart diseases. Paroxysms were interrupted by isolamid, tachmalin lidocain via slow intravenous infusion with constant ECG, auscultation and hemodynamic control, monitor follow up. The paroxysms successfully coped were 43. It proved possible to interrupt the rhythm disorders under the conditions of non-integrated polyclinic provided the functional consulting room is well equipped. The problem of early and effective treatment of rhythm disorders even under polyclinical conditions is solved, thus avoiding the unnecessary hospitalization of some of those patients and delay in the effective treatment of the other part of the patients. The early diagnosis and proper therapeutic behaviour of the physician towards the patient from the very first moment of contact to the transportation and hospitalization of the patient is of vital importance. The interruption of rhythm disorders must very cautiously be performed--the ventricular tachycardia and polytopic extrasystoles in particular, that considered only an introductory treatment.

The digital circulation in congestive heart failure.

Congestive heart failure (CHF) is a complex clinical entity which is still little understood pathophysiologically. Unless it is in the intractable state it responds well to therapy. It has been known for many years that the peripheral circulation can be dramatically altered when CHF is progressively and rapidly developing and worsening. As compensation develops, these changes gradually return to normal. We have long been studying the digital circulation of patients with CHF and have been impressed with the changes in the behavior of the peripheral blood vessels in these patients.

Treatment of paroxysmal supraventricular tachycardia in infancy with digitalis, adenosine-5'-triphosphate, and verapamil: a comparative study.

The treatment of paroxysmal supraventricular tachycardia (PSVT) in infancy with digitalis, adenosine triphosphate (ATP) and verapamil is reported. Treatment was successful in about 90% of the patients treated with ATP and verapamil and in 61--71% of the patients treated with digitalis (Lanatoside C). Verapamil terminated the tachycardia within 2 minutes of administration in most instances and ATP in less than 1 minute. Digitalis, however, took as long as 2 hours; it was therefore excluded as the drug of first choice in emergencies, and is better suited for treating patients with poor hemodynamics. Side effects with ATP are common but short-lived. With verapamil, side effects are rare, but may be serious if certain contraindications are not taken into account. Digitalis in the dose used in this trial rarely produced side effects. We conclude that ATP or verapamil is the drug of first choice for quick termination of PSVT in infancy.