Ethacrynic Acid is a potent, orally effective loop diuretic. Ethacrynic Acid reduces sodium and chloride reabsorption by inhibiting the Na+-K+-2Cl- cotransporter (NKCC2) in the thick ascending limb of the loop of Henle in renal tubules, thereby increasing urine output. Ethacrynic Acid can be used for the treatment of edematous conditions such as congestive heart failure, acute pulmonary edema, renal edema, and cirrhotic ascites[1-4].
In vitro, Ethacrynic Acid (0-80μM) was used to treat MCF7, MDA-MB-231, and 4T1 breast cancer cells for 24 hours. Ethacrynic Acid significantly inhibited cell proliferation in a concentration-dependent manner[5]. Ethacrynic Acid (75–100μM) was combined with Afatinib (2–6μM) to treat H1975 (EGFR L858R/T790M mutant) non-small cell lung cancer cells for 48 hours. Ethacrynic Acid significantly inhibited cell proliferation, arrested the cell cycle at the G2/M phase, induced apoptosis, and suppressed the activation of the WNT/β-catenin pathway[6].
In vivo, Ethacrynic Acid (1mg/kg or 10mg/kg) was intraperitoneally injected into male C57Bl/6 mice undergoing laparotomy at 6 hours and 0.5 hours before surgery, and at 6 hours and 12 hours after surgery. Ethacrynic Acid improved postoperative intestinal transit and reduced the expression of proinflammatory cytokines IL-6 and iNOS mRNA in the small intestinal wall[7]. Ethacrynic Acid (5mg/kg/day) was intraperitoneally injected daily into high-fat diet-induced obese (DIO) C57BL/6J mice for 8 weeks. Ethacrynic Acid significantly reduced body weight and adipose tissue, improved glucose tolerance and insulin sensitivity, increased energy expenditure, and promoted the browning of inguinal white adipose tissue[8].
References:
[1] Hinchcliff KW, Mitten LA. Furosemide, bumetanide, and ethacrynic acid. Vet Clin North Am Equine Pract. 1993 Dec;9(3):511-22.
[2] Cannon PJ, Kilcoyne MM. Ethacrynic acid and furosemide: renal pharmacology and clinical use. Prog Cardiovasc Dis. 1969 Jul;12(1):99-118.
[3] Kim KE, Onesti G, Moyer JH, et al. Ethacrynic acid and furosemide. Diuretic and hemodynamic effects and clinical uses. Am J Cardiol. 1971 Apr;27(4):407-15.
[4] Koechel DA. Ethacrynic acid and related diuretics: relationship of structure to beneficial and detrimental actions. Annu Rev Pharmacol Toxicol. 1981;21:265-93.
[5] Liu B, Huang X, Hu Y, et al. Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer. Oncotarget. 2016 Sep 6;7(36):58038-58050.
[6] Zhang X, Huang C, Cui B, et al. Ethacrynic Acid Enhances the Antitumor Effects of Afatinib in EGFR/T790M-Mutated NSCLC by Inhibiting WNT/Beta-Catenin Pathway Activation. Dis Markers. 2021 Apr 27;2021:5530673.
[7] Harada T, Fink M, Cruz RJ Jr, et al. Ethacrynic acid decreases expression of proinflammatory intestinal wall cytokines and ameliorates gastrointestinal stasis in murine postoperative ileus. Clinics (Sao Paulo). 2018 Oct 18;73:e332.
[8] Cui Z, Liu Y, Wan W, et al. Ethacrynic acid targets GSTM1 to ameliorate obesity by promoting browning of white adipocytes. Protein Cell. 2021 Jun;12(6):493-501.
Ethacrynic Acid是一种强效的、口服有效的袢利尿剂。Ethacrynic Acid通过抑制肾小管髓袢升支厚壁段的Na+-K+-2Cl-共转运体（NKCC2），减少钠和氯的重吸收，从而增加尿量。Ethacrynic Acid可用于水肿性疾病如充血性心力衰竭、急性肺水肿、肾性水肿、肝硬化腹水等的治疗[1-4]。
在体外，Ethacrynic Acid（0-80μM）处理MCF7、MDA-MB-231、4T1乳腺癌细胞24小时，Ethacrynic Acid显著抑制细胞增殖，且具有浓度依赖效应[5]。Ethacrynic Acid（75–100μM）与Afatinib（2–6μM）联合处理H1975（EGFR L858R/T790M突变型）非小细胞肺癌细胞48h。Ethacrynic Acid显著抑制细胞增殖、阻滞细胞周期于G2/M期、诱导细胞凋亡，并抑制WNT/β-catenin通路激活[6]。
在体内，Ethacrynic Acid（1mg/kg或10mg/kg）在手术前6小时、前0.5小时、手术后6小时及12小时腹腔注射于经历剖腹手术的雄性C57Bl/6小鼠。Ethacrynic Acid改善了术后肠道传输并降低了小肠壁促炎细胞因子IL-6和iNOS mRNA的表达[7]。Ethacrynic Acid（5mg/kg/day）每日腹腔注射于高脂饮食诱导的肥胖（DIO）C57BL/6J小鼠，连续8周。Ethacrynic Acid显著降低了小鼠的体重和脂肪组织，改善了葡萄糖耐量和胰岛素敏感性，增加了能量消耗，并促进了腹股沟白色脂肪组织的褐变[8]。