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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 -
JAMA Sep 1966
Topics: Ethacrynic Acid; Humans; Kidney Tubules
PubMed: 5953204
DOI: No ID Found -
Molecular Biology Reports Aug 2022Despite the recent advances in chemotherapy, the outcomes and the success of these treatments still remain insufficient. Novel combination treatments and treatment...
BACKGROUND
Despite the recent advances in chemotherapy, the outcomes and the success of these treatments still remain insufficient. Novel combination treatments and treatment strategies need to be developed in order to achieve more effective treatment. This study was designed to investigate the combined effect of ethacrynic acid and cinnamic acid on cancer cell lines.
METHODS
The anti-proliferative effect of ethacrynic acid and cinnamic acid was investigated by MTT cell viability assay in three different cancer cell lines. Combination indexes were calculated using CompuSyn software. Apoptosis was assessed by flow cytometric Annexin V-FITC/PI double-staining. The effect of the inhibitors on cell cycle distribution was measured by propidium iodide staining.
RESULTS
The combination treatment of ethacrynic acid and cinnamic acid decreased cell proliferation significantly, by 63%, 75% and 70% for K562, HepG2 and TFK-1 cells, respectively. A 5.5-fold increase in the apoptotic cell population was observed after combination treatment of K562 cells. The population of apoptotic cells increased by 9.3 and 0.4% in HepG2 and TFK-1 cells, respectively. Furthermore, cell cycle analysis shows significant cell cycle arrest in S and G2/M phase for K562 cells and non-significant accumulation in G0/G1 phase for TFK-1 and HepG2 cells.
CONCLUSIONS
Although there is a need for further investigation, our results suggest that the inhibitors used in this study cause a decrease in cellular proliferation, induce apoptosis and cause cell cycle arrest.
Topics: Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Cinnamates; Ethacrynic Acid; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 35585382
DOI: 10.1007/s11033-022-07560-5 -
The American Journal of Cardiology Apr 1971
Review
Topics: Animals; Anuria; Blood Pressure; Cardiac Output; Central Venous Pressure; Chlorides; Diuresis; Dogs; Edema; Ethacrynic Acid; Furosemide; Glomerular Filtration Rate; Heart Failure; Humans; Kidney; Kidney Glomerulus; Kidney Tubules; Potassium; Regional Blood Flow; Sodium; Vascular Resistance
PubMed: 4929423
DOI: 10.1016/0002-9149(71)90438-3 -
The Veterinary Clinics of North... Dec 1993Furosemide and, less commonly, bumetanide and ethacrynic acid are potent diuretics administered to horses for a variety of reasons, including prophylaxis of... (Review)
Review
Furosemide and, less commonly, bumetanide and ethacrynic acid are potent diuretics administered to horses for a variety of reasons, including prophylaxis of exercise-induced pulmonary hemorrhage. These drugs affect urine volume and composition, and furosemide has marked effects on plasma volume and composition and on systemic hemodynamics at rest and during exercise.
Topics: Animals; Bumetanide; Cardiovascular System; Doping in Sports; Ethacrynic Acid; Furosemide; Horses; Kidney; Physical Exertion; Plasma Volume; Respiration
PubMed: 8299013
DOI: 10.1016/s0749-0739(17)30383-8 -
Xenobiotica; the Fate of Foreign... Aug 19931. The diuretic drug ethacrynic acid (EA) is a potent reversible inhibitor of rat and human glutathione S-transferases (GST), with I50-values (microM) of 4.6-6.0,... (Review)
Review
1. The diuretic drug ethacrynic acid (EA) is a potent reversible inhibitor of rat and human glutathione S-transferases (GST), with I50-values (microM) of 4.6-6.0, 0.3-1.9 and 3.3-4.8 for alpha, mu and pi-class, respectively. 2. The reversible inhibition by the glutathione conjugate of EA is even stronger for alpha and mu-class, with I50-values (microM) of 0.8-2.8 and < 0.1-1.2, respectively, while the I50 for the pi-class is 11. 3. Inhibition of rat and human pi-class GST also occurs by covalent binding of ethacrynic acid. 14C-ethacrynic acid, 0.8 nmol EA per nmol pi-class GST could be incorporated, resulting in 65-93% inhibition of the catalytic activity. 4. Owing to the chemical nature of the covalent binding (Michael addition), this reaction should be reversible. Indeed, full restoration of the catalytic activity of GST P1-1 inactivated by covalently-bound EA was reached in about 125 h by incubation with an excess of glutathione. 5. EA has been used to inhibit GST in biological systems. The reversible covalent binding may very well play a role in the observed inhibition of GST by EA in vivo.
Topics: Animals; Ethacrynic Acid; Glutathione; Glutathione Transferase; Humans; Molecular Structure
PubMed: 8284946
DOI: 10.3109/00498259309059418 -
Biochemical Pharmacology Jun 2023Lung cancer is characterized by high incidence and mortality. 90% of cancer deaths are caused by metastases. The epithelial-mesenchymal transition (EMT) process in...
Lung cancer is characterized by high incidence and mortality. 90% of cancer deaths are caused by metastases. The epithelial-mesenchymal transition (EMT) process in cancer cells is a prerequisite for the metastatic process. Ethacrynic acid (ECA) is a loop diuretic that inhibits the EMT process in lung cancer cells. EMT has been related to the tumour immunemicroenvironment. However, the effect of ECA on immune checkpoint molecules in the context of cancer has not been fully identified. In the present study, we found that sphingosylphosphorylcholine (SPC) and TGF-β1, awell-known EMT inducer, induced the expression of B7-H4 in lung cancer cells. We also investigated the involvement of B7-H4 in the SPC-induced EMT process. Knockdown of B7-H4 suppressed SPC-induced EMT, while B7-H4 overexpression enhanced EMT of lung cancer cells. ECA inhibited SPC/TGF-β1-induced B7-H4 expression via suppression of STAT3 activation. Moreover, ECA inhibits the colonization of mice lung by tail vein-injected LLC1 cells. ECA-treated mice increased the CD4-positive T cells in lung tumour tissues. In summary, these results suggested that ECA inhibits B7-H4 expression via STAT3 inhibition, leading to SPC/TGF-β1-induced EMT. Therefore, ECA might be an immune oncological drug for B7-H4-positive cancer, especially lung cancer.
Topics: Animals; Mice; Transforming Growth Factor beta1; Ethacrynic Acid; Epithelial-Mesenchymal Transition; Cell Line, Tumor; Cell Movement; Adenocarcinoma of Lung; Lung Neoplasms
PubMed: 37019184
DOI: 10.1016/j.bcp.2023.115537 -
American Heart Journal Apr 1968
Topics: Ethacrynic Acid; Furosemide; Heart Failure; Humans; Liver Cirrhosis; Nephrosis
PubMed: 5647471
DOI: 10.1016/0002-8703(68)90016-1 -
Progress in Cardiovascular Diseases Jul 1969
Review
Topics: Edema; Ethacrynic Acid; Furosemide; Humans; Hypertension, Renal; Kidney; Potassium
PubMed: 4896962
DOI: 10.1016/0033-0620(69)90038-3