title: Valproic acid overcomes transforming growth factor-β-mediated sorafenib resistance in hepatocellular carcinoma.
abstract: Sorafenib is a multi-kinase inhibitor approved for hepatocellular carcinoma, but rarely causes tumor regression in patients with chronic liver diseases. To investigate whether growth factor-mediated signaling is involved in sorafenib resistance, HepG2 and PLC/PRF/5 hepatoma cells were exposed to epidermal growth factor (EGF), hepatocyte growth factor (HGF) or transforming growth factor-β (TGF-β) prior to treatment with sorafenib. Furthermore, to identify an effective combination treatment with sorafenib, growth factor-sensitized cells were treated with sorafenib alone or in combination with celecoxib, lovastatin or valproic acid (VPA). Trypan blue staining and Annexin V assays showed that the cytotoxic effect of sorafenib was inhibited by 15-54% in cells sensitized to TGF-β (P<0.05). Western blotting analysis showed that TGF-β significantly activated extracellular signal-regulated kinase (ERK)-mediated AKT signaling, and sorafenib failed to suppress both ERK and AKT in TGF-β-sensitized cells. The decreased anti-tumor effect of sorafenib was rescued by chemical inhibition of ERK and AKT. When TGF-β-sensitized cells were treated with sorafenib plus VPA, the levels of phosphorylated ERK and AKT were considerably suppressed and the numbers of dead cells were increased by 3.7-5.7-fold compared with those exposed to sorafenib alone (P<0.05). Moreover, low dose sorafenib-induced cell migration was effectively suppressed by combination treatment with sorafenib and VPA. Collectively, TGF-β/ERK/AKT signaling might play a critical role in sorafenib resistance in hepatoma cells, and combination treatment with VPA may be effective against this drug resistance.
authors.affiliation: Department of Medical Technology, Niigata University Graduate School of Health Sciences 2-746 Asahimachi-dori, Chuo-Ku, Niigata 951-8518, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Wakai
authors.affiliation: Division of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kubota
authors.affiliation: Division of Pediatric Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Osawa
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirose
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Sakata
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Medical Technology, Niigata University Graduate School of Health Sciences 2-746 Asahimachi-dori, Chuo-Ku, Niigata 951-8518, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Fujimaki
authors.affiliation: Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Takamura
authors.affiliation: Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamagiwa
authors.affiliation: Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences 1-757, Asahimachi-dori, Chuo-Ku, Niigata 951-8122, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Aoyagi
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D017211:Treatment Failure; D016896:Treatment Outcome; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D016212:Transforming Growth Factor beta; D009536:Niacinamide; D014635:Valproic Acid; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt
keywords: Sorafenib; TGF-β; hepatocellular carcinoma