Lipid droplet binding thalidomide analogs activate endoplasmic reticulum stress and suppress hepatocellular carcinoma in a chemically induced transgenic mouse model

Lajos I. Nagy, Eszter Molnár, Iván Kanizsai, Ramóna Madácsi, Béla Ózsvári, Liliána Z. Fehér, Gabriella Fábián, Annamária Marton, C. Vízler, F. Ayaydin, K. Kitajka, László Hackler, L. Mátés, Ferenc Deák, I. Kiss, L. Puskás

Research output: Contribution to journalArticle

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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. Conclusion: 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.

Original languageEnglish
Article number175
JournalLipids in Health and Disease
Volume12
Issue number1
DOIs
Publication statusPublished - Nov 22 2013

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Endoplasmic Reticulum Stress
Thalidomide
Transgenic Mice
Tumors
Hepatocellular Carcinoma
Liver
Lipids
Protein Disulfide-Isomerases
Neoplasms
Endpoint Determination
Affinity chromatography
Diethylnitrosamine
Confocal microscopy
Cell proliferation
Biosensing Techniques
Optical waveguides
Cell death
Unsaturated Fatty Acids
Affinity Chromatography
Biosensors

Keywords

  • Heat-shock proteins
  • Hepatocellular carcinoma
  • Lipid droplet
  • Protein disulfide isomerase
  • Reactive oxigen species

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Lipid droplet binding thalidomide analogs activate endoplasmic reticulum stress and suppress hepatocellular carcinoma in a chemically induced transgenic mouse model. / Nagy, Lajos I.; Molnár, Eszter; Kanizsai, Iván; Madácsi, Ramóna; Ózsvári, Béla; Fehér, Liliána Z.; Fábián, Gabriella; Marton, Annamária; Vízler, C.; Ayaydin, F.; Kitajka, K.; Hackler, László; Mátés, L.; Deák, Ferenc; Kiss, I.; Puskás, L.

In: Lipids in Health and Disease, Vol. 12, No. 1, 175, 22.11.2013.

Research output: Contribution to journalArticle

Nagy, Lajos I. ; Molnár, Eszter ; Kanizsai, Iván ; Madácsi, Ramóna ; Ózsvári, Béla ; Fehér, Liliána Z. ; Fábián, Gabriella ; Marton, Annamária ; Vízler, C. ; Ayaydin, F. ; Kitajka, K. ; Hackler, László ; Mátés, L. ; Deák, Ferenc ; Kiss, I. ; Puskás, L. / Lipid droplet binding thalidomide analogs activate endoplasmic reticulum stress and suppress hepatocellular carcinoma in a chemically induced transgenic mouse model. In: Lipids in Health and Disease. 2013 ; Vol. 12, No. 1.
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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. Conclusion: 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.",
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AU - Madácsi, Ramóna

AU - Ózsvári, Béla

AU - Fehér, Liliána Z.

AU - Fábián, Gabriella

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AU - Puskás, L.

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N2 - 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. Conclusion: 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.

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