BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) is one of the most effective single-drug systemic therapy against advanced HCC, but the identification of novel combination regimens for a continued improvement in overall survival is a big challenge. Recent studies highlighted the crucial role of focal adhesion kinase (FAK) in HCC growth. The aim of this study was to investigate the antitumor effects of three different FAK inhibitors (FAKi), alone or in combination with SOR, using in vitro and in vivo models of HCC. METHODS: The effect of PND1186, PF431396, TAE226 on cell viability was compared to SOR. Among them TAE226, emerging as the most effective FAKi, was tested alone or in combination with SOR using 2D/3D human HCC cell line cultures and HCC xenograft murine models. The mechanisms of action were assessed by gene/protein expression and imaging approaches, combined with high-throughput methods. RESULTS: TAE226 was the more effective FAKi to be combined with SOR against HCC. Combined TAE226 and SOR treatment reduced HCC growth both in vitro and in vivo by affecting tumour-promoting gene expression and inducing epigenetic changes via dysregulation of FAK nuclear interactome. We characterized a novel nuclear functional interaction between FAK and the NuRD complex. TAE226-mediated FAK depletion and SOR-promoted MAPK down-modulation caused a decrease in the nuclear amount of HDAC1/2 and a consequent increase of the histone H3 lysine 27 acetylation, thus counteracting histone H3 lysine 27 trimethylation. CONCLUSIONS: Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

• Klíčová slova
• Epigenetic, FAK, HCC, Sorafenib, Therapy,
• MeSH
• epigeneze genetická genetika   MeSH
• hepatocelulární karcinom farmakoterapie   MeSH
• lidé MeSH
• morfoliny farmakologie   terapeutické užití   MeSH
• myši inbrední NOD MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory jater farmakoterapie   MeSH
• proliferace buněk MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   terapeutické užití   MeSH
• sorafenib farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• morfoliny MeSH
• sorafenib MeSH
• TAE226 MeSH Prohlížeč

Ideal cardiovascular health (CVH) is defined for the presence of ideal behavioral and health metrics known to prevent cardiovascular disease (CVD). The association of circulatory phospho- and sphingo-lipids to primary reduction in cardiovascular risk is unclear. Our aim was to determine the association of CVH metrics with the circulating lipid profile of a population-based cohort. Serum sphingolipid and phospholipid species were extracted from 461 patients of the randomly selected prospective Kardiovize study based on Brno, Czech Republic. Lipids species were measured by a hyphenated mass spectrometry technique, and were associated with poor CVH scores, as defined by the American Heart Association. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE) species were significantly lower in ideal and intermediate scores of health dietary metric, blood pressure, total cholesterol and blood fasting glucose compared to poor scores. Current smokers presented higher levels of PC, PE and LPE individual species compared to non-smokers. Ceramide (Cer) d18:1/14:0 was altered in poor blood pressure, total cholesterol and fasting blood glucose metrics. Poor cardiovascular health metric is associated with a specific phospho- and sphingolipid pattern. Circulatory lipid profiling is a potential biomarker to refine cardiovascular health status in primary prevention strategies.

• Klíčová slova
• cardiovascular health, lipidomics, mass spectrometry, phospholipids, sphingolipids,
• Publikační typ
• časopisecké články MeSH