RESUMO
Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with γ-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24h treatment. No change in the Na,K-ATPase α1 isoform protein expression was detected. On the other hand it was 30-40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with γ-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives.
Assuntos
Antineoplásicos/síntese química , Compostos de Benzilideno/química , Digoxina/análogos & derivados , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Sítios de Ligação , Encéfalo/enzimologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Digoxina/síntese química , Digoxina/toxicidade , Células HeLa , Humanos , Rim/enzimologia , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Ratos , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
High-flow nasal cannula (HFNC) therapy is routinely used in the treatment of infants with bronchiolitis. This study sought to identify markers associated with failure of HFNC therapy that serve as warnings for early staging of other ventilatory support products. A retrospective study of infants with a diagnosis of bronchiolitis, receiving HFNC and admitted to the pediatric intensive care unit from January 2016 to June 2017, was conducted. The subjects were divided into two study groups according to the success or failure of HFNC therapy. Risk factors were assessed using the following variables: age, time between hospital admission and start of HFNC, equipment model, and the need for a nasogastric tube. Eighty-one infants were studied, and 18 (21.7%) of them exhibited therapy failure. The results of the logistic models showed that the chances of failure for patients requiring a nasogastric tube during HFNC use were more likely than those for patients with oral nutrition (OR = 8.17; 95% CI 2.30-28.99; p = 0.001). The HFNC failure was not associated with the device used (OR = 1.56; 95% CI 0.54-4.52; p = 0.41), time between hospital admission and HFNC installation (OR = 1.01; 95% CI 0.98-1.03; p = 0.73), or age (OR = 0.98; 95% CI 0.82-1.17; p = 0.82). Among late outcomes evaluated, the patients with therapy failure had longer total durations of O2 use (p < 0.001) and longer hospital stays (p < 0.001). The need to use a nasogastric tube during HFNC use was associated with HFNC therapy failure and can be considered as a marker of severity in children with bronchiolitis.