Ethacrynic acid inhibits STAT3 activity through the modulation of SHP2 and PTP1B tyrosine phosphatases in DU145 prostate carcinoma cells.

To identify signal transducer and activator of transcription factor 3 (STAT3) inhibitors, we generated STAT3-dependent gene expression signature by analyzing gene expression profiles of DU145 cancer cells treated with STAT3 inhibitor, piperlongumine and 2-hydroxycinnamaldehyde. Then we explored gene expression signature-based strategies using a connectivity map database and identified several STAT3 inhibitors, including ethacrynic acid (EA). EA is currently used as a diuretic drug. EA inhibited STAT3 activation in DU145 prostate cancer cells and consequently decreased the levels of STAT3 target genes such as cyclin A and MCL-1. Furthermore, EA treatment inhibited tumor growth in mice xenografted with DU145 cells and decreased p-STAT3 expression in tumor tissues. Knockdown of Src homology region 2 domain-containing phosphatase-2 (SHP2) or Protein tyrosine phosphatase 1B (PTP1B) gene expression by siRNA suppressed the ability of EA to inhibit STAT3 activation. When EA was combined with an activator of SHP2 or PTP1B, p-STAT3 expression was synergistically decreased; when EA was combined with an inhibitor of SHP2 or PTP1B, p-STAT3 expression was rescued. By using an affinity pulldown assay with biotinyl-EA, EA was shown to associate with SHP2 and PTP1B in vitro. Additionally, the drug affinity responsive target stability (DARTS) assay confirmed the direct binding of EA to SHP2 and PTP1B. SHP2 is activated by EA through active phosphorylation at Y580 and direct binding to SHP2. Collectively, our results suggest that EA inhibits STAT3 activity through the modulation of phosphatases such as SHP2 and PTP1B and may be a potential anticancer drug to target STAT3 in cancer progression.

Ototoxic drugs and sensorineural hearing loss following severe neonatal respiratory failure.

AIM: To determine relationships between ototoxic drugs and 4-y sensorineural hearing loss (SNHL) in near-term and term survivors of severe neonatal respiratory failure. METHODS: All 81 survivors of the Canadian arm of the Neonatal Inhaled Nitric Oxide Study (mortality 32, loss to follow-up 9) received loop diuretics, aminoglycosides, and neuromuscular blockers (NMB), and 50 received vancomycin as neonates. Prospective, longitudinal secondary outcome using audiological tests diagnosed late-onset, progressive SNHL in 43 (53%); not flat (sloping) in 29, flat (severe to profound) in 14. Risk for SNHL was determined. RESULTS: A combination of duration of diuretic use of >14 d and average NMB dose of >0.96 mg/kg/d contributed to SNHL among survivors (odds ratio 5.2; 95% CI 1.6, 16.7). Markers of illness severity did not contribute. Dosage or duration of aminoglycosides use did not relate to SNHL. Cumulative dosages and duration of use of diuretics; NMB; use of vancomycin; and overlap of diuretics with NMB, aminoglycosides, and vancomycin individually linked to SNHL (p<0.001). CONCLUSION: Overuse of loop diuretics and/or NMB contributes to SNHL after neonatal respiratory failure; markers of illness severity or the appropriate administration of aminoglycosides do not.

[Comparative effectiveness of the anti-inflammatory action of diuretics and butadione in an experiment]. / Sravnitel'naia éffektivnost' protivovospalitel'nogo deistviia diuretikov i butadiona v éksperimente.

Dichlothiazide and butadione were shown to attenuate equally the development of the rat paw inflammatory edema induced by subplantar dextran administration. Ethacrynic acid produced more pronounced antiedematous effect. Also, ethacrynic acid reduced to the highest degree the damp and dry mass of the inflammatory granuloma. Oxadoline and butadione considerably inhibit the formation of granuloma as well. The combined use of diuretics and butadione did not lead to a mutual potentiation of the antiinflammatory effect in exudative and proliferative inflammation.

[Effect of diuretics on the course of experimental arrhythmias]. / Vliianie diuretikov na techenie éksperimental'nykh aritmii.

The protective effect of triamterene was demonstrated on aconitine (rats) and strophanthin (cats) models of arrhythmias. Furosemide potentiates the antiarrhythmic effects of calcium chloride (rats) and strophanthin, ethacrynic acid potentiates the arrhythmogenic action of all agents used.

[Effect of diuretics on vascular permeability and proliferative inflammation in rats]. / Vliianie diuretikov na sosudistuiu pronitsaemost' i proliferativnoe vospalenie u krys.

It is shown that ethacrynic acid and dichlothiazide in 50 mg/kg dose reduce the dextran-induced increase of rat skin vascular permeability. Besides, durable administration of furosemide, dichlothiazide and ethacrynic acid in 50-80 mg/kg doses decreases the dry mass of inflammatory granuloma. This fact shows the ability of diuretics to suppress the development of proliferative inflammation.

[Effect of diuretics on the development of experimental inflammatory edema in rats]. / Vliianie diuretikov na razvitie éksperimental'nogo vospalitel'nogo oteka u krys.

Experiments on rats have shown that administration of furosemide, dichlothiazide and etacrinic acid (50 mg/kg intraperitoneally) reduced the development of experimental inflammatory edema caused by subplantar administration of 0.1 ml of 6% dextran or 10% ovalbumin. The antiedematous effect of the diuretics was preserved under the conditions of bilateral nephrectomy, which points to the presence of extrarenal mechanisms in the action of the drugs in experimental inflammation.

The use of diuretics in varying degrees of renal impairment: an overview.

Administration of diuretics during acute renal failure in animals has been demonstrated to be of value with mannitol and/or loop-blocking diuretics, furosemide or ethacrynic acid. There is evidence that if these drugs are given very early in the controlled experimental environment that there will be some beneficial effect in maintaining renal function. However, in man the temporal relationship between the acute onset and the successful response to the administration of the drugs is, at best, coincidental and the use of diuretics in acute renal failure may not produce the same results as seen in the laboratory. One of the best guides to the underlying disease when there is acute decompensation in renal function is the utility of the renal failure index which utilizes urine and plasma sodium and urine and plasma creatinine ratios. Large doses of loop-blocking diuretics can be of benefit in patients with mild to moderate chronic renal insufficiency and fluid retention and/or hypertension. When renal insufficiency is severe in the pre-dialysis setting, furosemide, bumetanide or muzolimine may be of some benefit; however, as renal failure worsens the response of the kidney is sluggish and it is wise to begin to dialyze when glomerular filtration deteriorates below 5 ml per minute.

[Treatment of hypercalcemias]. / Traitement des hypercalcémies.

Apart from the search for specific oncological treatments, interesting investigations are currently in progress into methods designed to increase bone resistance against tumoral aggression. Several substances are under study. Here the discussion will chiefly centre on the diphosphonates, their mechanism of action and indication in bone oncology. It has been seen that tumoral hypercalcemias (with or without bone metastases) essentially derive from disturbance of the balance between the huge mineral stores of the bone and the small extracellular space. It has also been learned that osteolysis inhibition is the major step in their treatment, while therapies designed to eliminate the calcium excess through the kidney (saline solutions, furosemide, ethacrinic acid, dialysis) or bind it with chelators (EDTA) can have only transitory effects. Tumoral osteolysis may be inhibited by drugs acting on bone and/or tumoral cells (mithramycin, calcitonin, corticosteroids etc.) or by the diphosphonates. At present the latter are the treatment of choice for tumoral hypercalcemias.

Diuretics.

The use of diuretics to treat edema is reviewed. Normal salt and water metabolism is reviewed briefly. The drugs covered are the thiazide diuretics, loop diuretics(ethacrynic acid and furosemide) and distal blocking agents (spironolactone and triamterene). The sites and modes of action, indications, doses, complications and relative costs of these agents are discussed.