title: New therapeutic strategy for hepatocellular carcinoma by molecular targeting agents via inhibition of cellular stress defense mechanisms.
abstract: The prognosis of advanced hepatocellular carcinoma (HCC) has remained very poor.It has recently been reported that the molecular targeting agent sorafenib can improve the prognosis of patients with advanced HCC. However, the detailed mechanisms of sorafenib, especially its direct effects on hepatoma and hepatocyte cells, are poorly understood, making a more detailed investigation about the molecular mechanism of sorafenib necessary. Endoplasmic reticulum (ER) stress is related to the pathophysiology of various liver diseases, including chronic viral hepatitis, alcoholic and nonalcoholic steatohepatitis and HCC. In this regard, our recent data examining the molecular effects of sorafenib focused on the cellular defense mechanisms from ER stress, the unfolded protein response (UPR) and keratin phosphorylation, demonstrated that sorafenib inhibited both important cytoprotective mechanisms, UPR and keratin phosphorylation, and enhances the anti-tumor effect in combination with proteasome inhibitors. This review summarizes the cytoprotective mechanisms from ER stress and our results about the direct effect of sorafenib on the cytoprotective mechanisms.
authors.affiliation: Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Honma
authors.forename: Masaru
authors.initials: M
authors.lastname: Harada
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D019610:Cytoprotection / Q000187:drug effects* / Q000235:genetics*; D004359:Drug Therapy, Combination; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000077157:Sorafenib; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D061988:Proteasome Inhibitors; D009536:Niacinamide; D007633:Keratins; D000077157:Sorafenib