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RESEARCH PRODUCT
Fasting inhibits hepatic stellate cells activation and potentiates anti-cancer activity of Sorafenib in hepatocellular cancer cells
Valerio PazienzaCarlo CerviStefania PortoConcetta PanebiancoOriana Lo ReManlio VinciguerraFrancesca RappaStefano Di BiaseMichele Caragliasubject
0301 basic medicineSorafenibLipopolysaccharidesNiacinamidemedicine.medical_specialtyCirrhosisCarcinoma HepatocellularTime FactorsPhysiologyGlucose uptakeClinical BiochemistryAntineoplastic AgentsLiver Cirrhosis Experimental03 medical and health sciencesFibrosisNon-alcoholic Fatty Liver DiseaseInternal medicineSorafenib fastingmedicineHepatic Stellate CellsAnimalsHumansneoplasmsCell Proliferationhepatic stellate cellDose-Response Relationship Drugbusiness.industryMedicine (all)Phenylurea CompoundsLiver NeoplasmsCancerCell BiologyFastingHep G2 Cellshepatocellular carcinomaSorafenibmedicine.diseasedigestive system diseasesGene Expression Regulation NeoplasticMice Inbred C57BL030104 developmental biologyEndocrinologyGlucoseHepatocellular carcinomaHepatic stellate cellCancer researchSteatohepatitisbusinessmedicine.drugdescription
BACKGROUND: Hepatocellular carcinoma (HCC) has a poor outcome. Most HCCs develop in the context of liver fibrosis and cirrhosis caused by chronic inflammation. Short-term fasting approaches enhance the activity of chemotherapy in preclinical cancer models, other than HCC. Multi-tyrosine kinase inhibitor Sorafenib is the mainstay of treatment in HCC. However, its benefit is frequently short-lived. Whether fasting can alleviate liver fibrosis and whether combining fasting with Sorafenib is beneficial remains unknown. METHODS: 24 hour fasting (2% serum, 0.1% glucose)-induced changes on human hepatic stellate cells (HSC) LX-2 proliferation/viability/cell cycle were assessed by MTT and flow cytometry. Expression of lypolysaccharide (LPS)-induced activation markers (vimentin, αSMA) was evaluated by qPCR and immunoblotting. Liver fibrosis and inflammation were evaluated in a mouse model of steatohepatitis exposed to cycles of fasting, by histological and biochemical analyses. 24 hours fasting-induced changes were also analyzed on the proliferation/viability/glucose uptake of human HCC cells exposed to Sorafenib. An expression panel of genes involved in survival, inflammation and metabolism was examined by qPCR in HCC cells exposed to fasting and/or Sorafenib. RESULTS: Fasting decreased the proliferation and the activation of HSC. Repeated cycles of short-term starvation were safe in mice but did not improve fibrosis. Fasting synergized with Sorafenib in hampering HCC cell growth and glucose uptake. Finally, fasting normalized the expression levels of genes which are commonly altered by Sorafenib in HCC cells. CONCLUSIONS: Fasting or fasting-mimicking diet diets should be evaluated in preclinical studies as a mean to potentiate the activity of Sorafenib in clinical use. This article is protected by copyright. All rights reserved
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-03-13 |