title: Sorafenib enhances the chemotherapeutic efficacy of S-1 against hepatocellular carcinoma through downregulation of transcription factor E2F-1.
abstract: OBJECTIVE
  Sorafenib and S-1 (one mixed formulation containing 5-FU prodrug and dihydropyrimidine dehydrogenase inhibitor) were two effective agents against hepatocellular carcinoma (HCC), but whether they had synergistic effects remained unclear. The present study aimed at evaluating their synergistic effects against HCC and its mechanisms.
  
  
  METHODS
  Inhibitory effects of sorafenib, 5-FU and their combination on HCC cells PLC/PRF/5 and SK-HEP-1 were evaluated. Expressions of transcription factor E2F-1 and its downstream thymidylate synthetase (TS) in the treated cells were determined using real-time PCR and Western blot. In vivo anti-tumoral efficacy of S-1 plus sorafenib on HCC was evaluated in NOD/SCID mice. E2F-1 and TS expressions in tumors were determined by immunohistochemical staining.
  
  
  RESULTS
  Sorafenib inhibited growth of HCC cells in dose-dependent manner, with IC50 of 5.4 ± 0.3 μmol/L for PLC/PRF/5 and 5.3 ± 0.5 μmol/L for SK-HEP-1. Sorafenib (1 μmol/L) enhanced inhibitory efficacy of 5-FU on HCC cells in vitro, dropping IC50 of 5-FU from 167.7 ± 12.1 to 105.4 ± 8.4 μmol/L for PLC/PRF/5 and 115 ± 10.2 to 82 ± 7.4 μmol/L for SK-HEP-1 (both p < 0.01). Sorafenib downregulated E2F-1 and TS expressions on HCC cells, and its combination with 5-FU yielded a synergistic downregulation of TS expression on HCC cells. In NOD/SCID mice with subcutaneously inoculated HCC, sorafenib combined with S-1 yielded greater inhibition on tumor growth and remarkable TS suppression when compared with sorafenib or S-1 alone (all p < 0.05).
  
  
  CONCLUSIONS
  Sorafenib enhanced therapeutic efficacy of 5-FU/S-1 against HCC through downregulation of E2F-1 and TS expressions. Sorafenib combined with S-1 might represent as valuable therapeutic regimen against HCC.
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China.
authors: Jing-Ming
authors: JM
authors: Zhai
authors: Xiao-Yu
authors: XY
authors: Yin
authors: Ying-Rong
authors: YR
authors: Lai
authors: Xun
authors: X
authors: Hou
authors: Jian-Peng
authors: JP
authors: Cai
authors: Xiao-Yi
authors: XY
authors: Hao
authors: Li-Jian
authors: LJ
authors: Liang
authors: Long-Juan
authors: LJ
authors: Zhang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004338:Drug Combinations; D004357:Drug Synergism; D050687:E2F1 Transcription Factor / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010094:Oxonic Acid / Q000008:administration & dosage; D010671:Phenylurea Compounds / Q000008:administration & dosage; D060888:Real-Time Polymerase Chain Reaction; D000077157:Sorafenib; D005641:Tegafur / Q000008:administration & dosage; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D004338:Drug Combinations; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D010671:Phenylurea Compounds; C079198:S 1 (combination); D005641:Tegafur; D009536:Niacinamide; D010094:Oxonic Acid; D000077157:Sorafenib; D013940:Thymidylate Synthase