title: Lipid droplet binding thalidomide analogs activate endoplasmic reticulum stress and suppress hepatocellular carcinoma in a chemically induced transgenic mouse model.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and it has limited treatment options.
  
  
  RESULTS
  In this study, we report the in vitro and in vivo effects of two novel amino-trifluoro-phtalimide analogs, Ac-915 and Ac-2010. Both compounds bind lipid droplets and endoplasmic reticulum membrane, and interact with several proteins with chaperone functions (HSP60, HSP70, HSP90, and protein disulfide isomerase) as determined by affinity chromatography and resonant waveguide optical biosensor technology. Both compounds inhibited protein disulfide isomerase activity and induced cell death of different HCC cells at sub or low micromolar ranges detected by classical biochemical end-point assay as well as with real-time label-free measurements. Besides cell proliferation inhibiton, analogs also inhibited cell migration even at 250 nM. Relative biodistribution of the analogs was analysed in native tissue sections of different organs after administration of drugs, and by using fluorescent confocal microscopy based on the inherent blue fluorescence of the compounds. The analogs mainly accumulated in the liver. The effects of Ac-915 and Ac-2010 were also demonstrated on the advanced stages of hepatocarcinogenesis in a transgenic mouse model of N-nitrosodiethylamine (DEN)-induced HCC. Significantly less tumor development was found in the livers of the Ac-915- or Ac-2010-treated groups compared with control mice, characterized by less liver tumor incidence, fewer tumors and smaller tumor size.
  
  
  CONCLUSIONS
  These results imply that these amino-trifluoro-phthalimide analogs could serve potent clinical candidates against HCC alone or in combination with dietary polyunsaturated fatty acids.
authors.forename: Lajos I
authors.initials: LI
authors.lastname: Nagy
authors.forename: Eszter
authors.initials: E
authors.lastname: Molnár
authors.forename: Iván
authors.initials: I
authors.lastname: Kanizsai
authors.forename: Ramóna
authors.initials: R
authors.lastname: Madácsi
authors.forename: Béla
authors.initials: B
authors.lastname: Ózsvári
authors.forename: Liliána Z
authors.initials: LZ
authors.lastname: Fehér
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fábián
authors.forename: Annamária
authors.initials: A
authors.lastname: Marton
authors.forename: Csaba
authors.initials: C
authors.lastname: Vizler
authors.forename: Ferhan
authors.initials: F
authors.lastname: Ayaydin
authors.forename: Klára
authors.initials: K
authors.lastname: Kitajka
authors.forename: László
authors.initials: L
authors.lastname: Hackler
authors.forename: Lajos
authors.initials: L
authors.lastname: Mátés
authors.forename: Ferenc
authors.initials: F
authors.lastname: Deák
authors.forename: Ibolya
authors.initials: I
authors.lastname: Kiss
authors.affiliation: AVIDIN Ltd,, Szeged, Hungary. puskas.szbk@gmail.com.
authors.forename: László G
authors.initials: LG
authors.lastname: Puskás
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism; D004052:Diethylnitrosamine; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018834:Chaperonin 60; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C557066:Hspd1 protein, mouse; D008055:Lipids; D024101:Mitochondrial Proteins; D004052:Diethylnitrosamine; D013792:Thalidomide