RESUMEN
The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profound reprogramming of mitochondria function and marked activation of genes required for mitochondrial protein translation and biogenesis. Mitochondrial ribosomal proteins and components of translation and import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patients show similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated (pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionable target to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727, reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. These results sustain the importance of mitochondria plasticity in response to sorafenib and identify a clinically actionable strategy for improving the treatment efficacy in HCC patients.
RESUMEN
A new tool for the measurement of TOC based on the heterogeneous photocatalysis activated by two different light sources has been planned. The instrument is constituted by a cell where the degradation occurs thanks to both the UV irradiation and the presence of a powered catalyst and by a measurement cell lodging CO2 gas permeable membrane electrode (detector), thermometer, inlet and outlet ways for the samples. One of the sources has a maximum emission at 254nm, while the other simulates the solar spectrum. A suspension (1 g/L) of titanium dioxide (Degussa P25) has been used to catalyse the process. A magnetic stirrer and a circulating pump avoid the deposition of the catalyst on the bottom of the reactor. The online measurement of produced CO2 was performed on 11 molecules (commercial names: Parachlorophenol, D-Glucose, Acid Blue 29, Atraton, Aspirin, Dimethoate, Aldicarb sulfone, Hydroquinone, (R)-Propranolol, Citric acid, Atrazine) to test the system efficiency. The experimental CO2 value was compared with the theoretical TOC value calculated by means of the structure's formula.