RESUMEN
OBJECTIVE: Extravasation of circulating cancer cells is an important step of the metastatic cascade and a potential target for anti-cancer strategies based on vasoprotective drugs. Reports on anti-cancer effects of fenofibrate (FF) prompted us to analyze its influence on the endothelial barrier function during prostate cancer cell diapedesis. RESEARCH DESIGN AND METHODS: In vitro co-cultures of endothelial cells with cancer cells imitate the 'metastatic niche' in vivo. We qualitatively and quantitatively estimated the effect of 25 µM FF on the events which accompany prostate carcinoma cell diapedesis, with the special emphasis on endothelial cell mobilization. RESULTS: Fenofibrate attenuated cancer cell diapedesis via augmenting endothelial cell adhesion to the substratum rather than through the effect on intercellular communication networks within the metastatic niche. The inhibition of endothelial cell motility was accompanied by the activation of PPARα-dependent and PPARα-independent reactive oxygen species signaling, Akt and focal adhesion kinase (FAK) phosphorylation, in the absence of cytotoxic effects in endothelial cells. CONCLUSIONS: Fenofibrate reduces endothelial cell susceptibility to the paracrine signals received from prostate carcinoma cells, thus inhibiting endothelial cell mobilization and reducing paracellular permeability of endothelium in the metastatic niche. Our data provide a mechanistic rationale for extending the clinical use of FF and for the combination of this well tolerated vasoactive drug with the existing multidrug regimens used in prostate cancer therapy.
Asunto(s)
Células Endoteliales/efectos de los fármacos , Fenofibrato/farmacología , PPAR alfa/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Adhesión Celular/efectos de los fármacos , Comunicación Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Técnicas de Cocultivo , Células Endoteliales/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Masculino , Metástasis de la Neoplasia/prevención & control , Fosforilación/efectos de los fármacos , Neoplasias de la Próstata/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Chronic inflammation of the airways and structural changes in the bronchial wall are basic hallmarks of asthma. Human bronchial fibroblasts derived from patients with diagnosed asthma display in vitro predestination towards TGF-ß-induced fibroblast-to-myofibroblast transition (FMT), a key event in the bronchial wall remodelling. Statins inhibit 3-hydroxymethyl-3-glutaryl coenzyme A reductase, a key enzyme in the cholesterol synthesis pathway and are widely used as antilipidemic drugs. The pleiotropic anti-inflammatory effects of statins, independent of their cholesterol-lowering capacity, are also well established. Since commonly used anti-asthmatic drugs do not reverse the structural remodelling of the airways and statins have tentative anti-asthmatic activity, we have studied the effect of lovastatin on FMT in populations of human bronchial fibroblasts derived from asthmatic patients. We demonstrate that the intensity of FMT induced by TGF-ß1 was strongly and dose-dependently attenuated by lovastatin. Furthermore, we show that neither the suppression of prenylation of signalling proteins nor the effect on reactive oxygen species formation are important for lovastatin-induced inhibition of myofibroblast differentiation. On the other hand, we show that a squalene synthase inhibitor, zaragozic acid A, reduced the TGF-ß1-induced FMT to an extent comparable to lovastatin effect. Additionally we demonstrate that in bronchial fibroblast populations, both inhibitors (lovastatin and zaragozic acid A) attenuate the TGF-ß1-induced Smad2 nuclear translocation in a manner dependent on intracellular cholesterol level. Our data suggest that statins can directly, by decrease of intracellular cholesterol level, affect basic cell signalling events crucial for asthmatic processes and potentially prevent perilous bronchial wall remodelling associated with intensive myofibroblast formation.