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Oncology Letters Nov 2018Once aberrantly activated, the Wnt/β-catenin pathway may result in uncontrolled proliferation and eventually cancer. Efforts to counter and inhibit this pathway are...
Once aberrantly activated, the Wnt/β-catenin pathway may result in uncontrolled proliferation and eventually cancer. Efforts to counter and inhibit this pathway are mainly directed against β-catenin, as it serves a role on the cytoplasm and the nucleus. In addition, specially-generated lymphocytes are recruited for the purpose of treating liver cancer. Peripheral blood mononuclear lymphocytes are expanded by the timely addition of interferon γ, interleukin (IL)-1β, IL-2 and anti-cluster of differentiation 3 antibody. The resulting cells are called cytokine-induced killer (CIK) cells. The present study utilised these cells and combine them with drugs inhibiting the Wnt pathway in order to examine whether this resulted in an improvement in the killing ability of CIK cells against liver cancer cells. Drugs including ethacrynic acid (EA) and ciclopirox olamine (CPX) were determined to be suitable candidates, as determined by previous studies. Drugs were administered on their own and combined with CIK cells and then a cell viability assay was performed. These results suggest that EA-treated cells demonstrated apoptosis and were significantly affected compared with untreated cells. Unlike EA, CPX killed normal and cancerous cells even at low concentrations. Subsequent to combining EA with CIK cells, the potency of killing was increased and a greater number of cells died, which proves a synergistic action. In summary, EA may be used as an anti-hepatocellular carcinoma drug, while CPX possesses a high toxicity to cancerous as well as to normal cells. It was proposed that EA should be integrated into present therapeutic methods for cancer.
PubMed: 30405829
DOI: 10.3892/ol.2018.9472 -
BMC Pharmacology & Toxicology Jun 2022Ethacrynic acid (EA) is a loop diuretic that is approved orally and parenterally to manage edema-associated diseases. Nevertheless, it was earlier reported that it is...
BACKGROUND
Ethacrynic acid (EA) is a loop diuretic that is approved orally and parenterally to manage edema-associated diseases. Nevertheless, it was earlier reported that it is also associated with bleeding upon its parenteral administration. In this report, we investigated the effects of EA on human factor XIIIa (FXIIIa) of the coagulation process using a variety of techniques.
METHODS
A series of biochemical and computational methods have been used in this study. The potency and efficacy of human FXIIIa inhibition by EA was evaluated using a bisubstrate-based fluorescence trans-glutamination assay under near physiological conditions. To establish the physiological relevance of FXIIIa inhibition by EA, the effect on FXIIIa-mediated polymerization of fibrin(ogen) as well as the formation of fibrin(ogen) - α-antiplasmin complex was evaluated using SDS-PAGE experiments. The selectivity profile of EA against other coagulation proteins was assessed by evaluating EA's effect on human clotting times in the activated partial thromboplastin time (APTT) and the prothrombin time (PT) assays. We also used molecular modeling studies to put forward a putative binding mode for EA in the active site of FXIIIa. Results involving EA were the average of at least three experiments and the standard error ± 1 was provided. In determining the inhibition parameters, we used non-linear regression analysis.
RESULTS
FXIIIa is a transglutaminase that works at the end of the coagulation process to form an insoluble, rigid, and cross-linked fibrin rich blood clot. In fact, inhibition of FXIIIa-mediated biological processes has been reported to result in a bleeding diathesis. Inhibition of FXIIIa by EA was investigated given the nucleophilic nature of the thiol-containing active site of the enzyme and the Michael acceptor-based electrophilicity of EA. In a bisubstrate-based fluorescence trans-glutamination assay, EA inhibited FXIIIa with a moderate potency (IC ~ 105 µM) and efficacy (∆Y ~ 66%). In SDS-PAGE experiments, EA appears to significantly inhibit the FXIIIa-mediated polymerization of fibrin(ogen) as well as the formation of fibrin(ogen) - α-antiplasmin complex which indicates that EA affects the physiological functions of FXIIIa. Interestingly, EA did not affect the clotting times of human plasma in the APTT and the PT assays at the highest concentration tested of 2.5 mM suggesting the lack of effects on the coagulation serine proteases and potentially the functional selectivity of EA with respect to the clotting process. Molecular modeling studies demonstrated that the Michael acceptor of EA forms a covalent bond with catalytic residue of Cys314 in the active site of FXIIIa.
CONCLUSIONS
Overall, our studies indicate that EA inhibits the physiological function of human FXIIIa in vitro which may potentially contribute to the bleeding complications that were reported with the association of the parenteral administration of EA.
Topics: Antifibrinolytic Agents; Blood Coagulation; Ethacrynic Acid; Factor XIIIa; Fibrin; Humans
PubMed: 35642005
DOI: 10.1186/s40360-022-00575-5 -
American Journal of Physiology. Renal... Dec 2020Similar to other organs, renal lymphatics remove excess fluid, solutes, and macromolecules from the renal interstitium. Given the kidney's unique role in maintaining...
Similar to other organs, renal lymphatics remove excess fluid, solutes, and macromolecules from the renal interstitium. Given the kidney's unique role in maintaining body fluid homeostasis, renal lymphatics may be critical in this process. However, little is known regarding the pathways involved in renal lymphatic vessel function, and there are no studies on the effects of drugs targeting impaired interstitial clearance, such as diuretics. Using pressure myography, we showed that renal lymphatic collecting vessels are sensitive to changes in transmural pressure and have an optimal range of effective pumping. In addition, they are responsive to vasoactive factors known to regulate tone in other lymphatic vessels including prostaglandin E and nitric oxide, and their spontaneous contractility requires Ca and Cl. We also demonstrated that Na-K-2Cl cotransporter Nkcc1, but not Nkcc2, is expressed in extrarenal lymphatic vessels. Furosemide, a loop diuretic that inhibits Na-K-2Cl cotransporters, induced a dose-dependent dilation in lymphatic vessels and decreased the magnitude and frequency of spontaneous contractions, thereby reducing the ability of these vessels to propel lymph. Ethacrynic acid, another loop diuretic, had no effect on vessel tone. These data represent a significant step forward in our understanding of the mechanisms underlying renal lymphatic vessel function and highlight potential off-target effects of furosemide that may exacerbate fluid accumulation in edema-forming conditions.
Topics: Animals; Calcium; Chlorides; Furosemide; Kidney; Lymphatic Vessels; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pressure; Rats; Rats, Sprague-Dawley; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 33103446
DOI: 10.1152/ajprenal.00322.2020 -
Journal of Otology Dec 2016Over the past two decades considerable progress has been made in understanding the ototoxic effects and mechanisms underlying loop diuretics. As typical representative... (Review)
Review
Over the past two decades considerable progress has been made in understanding the ototoxic effects and mechanisms underlying loop diuretics. As typical representative of loop diuretics ethacrynic acid or furosemide only induces temporary hearing loss, but rarely permanent deafness unless applied in severe acute or chronic renal failure or with other ototoxic drugs. Loop diuretic induce unique pathological changes in the cochlea such as formation of edematous spaces in the epithelium of the stria vascularis, which leads to rapid decrease of the endolymphatic potential and eventual loss of the cochlear microphonic potential, summating potential, and compound action potential. Loop diuretics interfere with strial adenylate cyclase and Na+/K+-ATPase and inhibit the Na-K-2Cl cotransporter in the stria vascularis, however recent reports indicate that one of the earliest effects is to abolish blood flow in the vessels supplying the lateral wall. Since ethacrynic acid does not damage the stria vascularis in vitro, the changes in Na+/K+-ATPase and Na-K-2Cl seen may be secondary effects results from strial ischemia and anoxia. Recent observations showing that renin is present in pericytes surrounding stria arterioles suggest that diuretics may induce local vasoconstriction by renin secretion and angiotensin formation. The tight junctions in the blood-cochlea barrier prevent toxic molecules and pathogens from entering cochlea, but when diuretics induce a transient ischemia, the barrier is temporarily disrupted allowing the entry of toxic chemicals or pathogens.
PubMed: 29937824
DOI: 10.1016/j.joto.2016.10.001 -
International Journal of Molecular... Apr 2023Ethacrynic acid (ECA) is a diuretic that inhibits Na-K-2Cl cotransporter (NKCC2) present in the thick ascending loop of Henle and muculo dens and is clinically used for... (Review)
Review
Ethacrynic acid (ECA) is a diuretic that inhibits Na-K-2Cl cotransporter (NKCC2) present in the thick ascending loop of Henle and muculo dens and is clinically used for the treatment of edema caused by excessive body fluid. However, its clinical use is limited due to its low bioavailability and side effects, such as liver damage and hearing loss at high doses. Despite this, ECA has recently emerged as a potential anticancer agent through the approach of drug repositioning, with a novel mechanism of action. ECA has been shown to regulate cancer hallmark processes such as proliferation, apoptosis, migration and invasion, angiogenesis, inflammation, energy metabolism, and the increase of inhibitory growth factors through various mechanisms. Additionally, ECA has been used as a scaffold for synthesizing a new material, and various derivatives have been synthesized. This review explores the potential of ECA and its derivatives as anticancer agents, both alone and in combination with adjuvants, by examining their effects on ten hallmarks of cancer and neuronal contribution to cancer. Furthermore, we investigated the trend of synthesis research of a series of ECA derivatives to improve the bioavailability of ECA. This review highlights the importance of ECA research and its potential to provide a cost-effective alternative to new drug discovery and development for cancer treatment.
Topics: Humans; Ethacrynic Acid; Drug Repositioning; Diuretics; Edema; Antineoplastic Agents
PubMed: 37047688
DOI: 10.3390/ijms24076712 -
British Medical Journal Nov 1966
Topics: Ethacrynic Acid
PubMed: 5917840
DOI: No ID Found -
The Cochrane Database of Systematic... Feb 2015Blood transfusions are associated with significant morbidity and mortality. Prophylactic administration of loop diuretics (furosemide, bumetanide, ethacrynic acid, or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Blood transfusions are associated with significant morbidity and mortality. Prophylactic administration of loop diuretics (furosemide, bumetanide, ethacrynic acid, or torsemide) is common practice, especially among people who are at risk for circulatory overload, pulmonary oedema or both.
OBJECTIVES
This review aimed to determine if the prophylactic administration of loop diuretics (furosemide, bumetanide, ethacrynic acid, or torsemide) provides a therapeutic advantage (that is, a favourable risk benefit ratio) in adults and children who are recipients of any blood product transfusion versus placebo, no treatment, or general fluid restriction measures.
SEARCH METHODS
We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
SELECTION CRITERIA
All randomised controlled trials (RCTs) and quasi-RCTs assessing a loop diuretic in patients receiving any blood transfusion were considered for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed study quality and extracted data. Study authors were contacted for additional information. Results were to be expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Mean effect sizes were to be calculated using the random-effects models.
MAIN RESULTS
We included four studies that involved 100 participants. Furosemide was the only diuretic investigated in all four studies.None of the included studies assessed the clinically important outcomes noted in our protocol. The studies focused on various markers of respiratory function. An improvement in fraction of inspired oxygen (in favour of furosemide) was noted in one study. An improvement in pulmonary capillary wedge pressure (in favour of furosemide) was noted in two studies.
AUTHORS' CONCLUSIONS
There was insufficient evidence to determine whether premedicating people undergoing blood transfusion with loop diuretics prevents clinically important transfusion-related morbidity. Due to the continued use of prophylactic loop diuretics during transfusions, and because this review highlights the absence of evidence to justify this practice, well-conducted RCTs are needed. Given the high mortality, severe morbidity and increasing incidence of transfusion-associated circulatory overload, determining the therapeutic utility of pre-transfusion loop diuresis is an urgent need.
Topics: Adult; Body Water; Confidence Intervals; Furosemide; Humans; Infant, Newborn; Infant, Premature; Pulmonary Edema; Randomized Controlled Trials as Topic; Sodium Potassium Chloride Symporter Inhibitors; Transfusion Reaction
PubMed: 25685898
DOI: 10.1002/14651858.CD010138.pub2