RESUMO
Hepatitis C virus (HCV) infection has been related to increased risk of development of hepatocellular carcinoma (HCC) while metformin (M) and statins treatment seemed to protect against HCC development. In this work, we aim to identify the mechanisms by which metformin and simvastatin (S) could protect from liver cancer. Huh7.5 cells were infected with HCV particles and treated with M+S. Human primary hepatocytes were treated with M+S. Treatment with both drugs inhibited Huh7.5 cell growth and HCV infection. In non-infected cells S increased translational controlled tumor protein (TCTP) and phosphatase and tensin homolog (PTEN) proteins while M inhibited mammalian target of rapamycin (mTOR) and TCTP. Simvastatin and metformin co-administered down-regulated mTOR and TCTP, while PTEN was increased. In cells infected by HCV, mTOR, TCTP, p62 and light chain 3B II (LC3BII) were increased and PTEN was decreased. S+M treatment increased PTEN, p62 and LC3BII in Huh7.5 cells. In human primary hepatocytes, metformin treatment inhibited mTOR and PTEN, but up-regulated p62, LC3BII and Caspase 3. In conclusion, simvastatin and metformin inhibited cell growth and HCV infection in vitro. In human hepatocytes, metformin increased cell-death markers. These findings suggest that M+S treatment could be useful in therapeutic prevention of HCV-related hepatocellular carcinoma.
Assuntos
Hepacivirus/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Metformina/administração & dosagem , PTEN Fosfo-Hidrolase/metabolismo , Sinvastatina/administração & dosagem , Serina-Treonina Quinases TOR/genética , Autofagia/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/prevenção & controle , Caspase 3/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimioterapia Combinada , Expressão Gênica/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/prevenção & controle , Proteínas Associadas aos Microtúbulos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína Tumoral 1 Controlada por TraduçãoRESUMO
Low-phospholipid-associated cholelithiasis syndrome (LPAC) is associated with ABCB4 genetic mutation. ABCB4 encodes MDR3 protein, involved in biliary phosphatidylcholine excretion.Higher prevalence in women, biliary symptoms in young adults and ursodesoxycholic acid (UDCA) response are the main features. We report the case of a 48-year-old man with hepatitis C, genotype 1b, fibrosis F3, null responder to Peg-IFN-alpha-2b/ribavirin and nephritic colic. In 2011 he developed jaundice, pruritus and epigastric pain.He showed increased serum levels of AST, ALT, GGT, bilirubin and alpha-fetoprotein, and viral load (14,600,000 IU/mL). Pancreatic- CT, endoscopic ultrasonography and echo-Doppler showed noncirrhotic chronic liver disease. The episode resolved spontaneously and one year later he suffered a similar episode. UDCA was started with excellent response. An immunohistochemistry study and sequencing of ABCB4 did not find alteration. MLPA® technique detected heterozygous deletion of the full exon 4 confirming LPAC syndrome diagnosis.
