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

Lipids in Health and Disease

Research

Gabriella Fábián¹  Eszter Molnár¹  Béla Ózsvári²  Lajos I Nagy²  László Hackler²  Iván Kanizsai²  Ramóna Madácsi²  Liliána Z Fehér²  László G Puskás³  Ibolya Kiss⁴  Klára Kitajka⁵  Csaba Vizler⁶  Ferenc Deák⁶  Annamária Marton⁶  Lajos Mátés⁷  Ferhan Ayaydin⁸ 

[1] AVICOR Ltd., Szeged, Hungary;AVIDIN Ltd., Szeged, Hungary;AVIDIN Ltd., Szeged, Hungary;AVICOR Ltd., Szeged, Hungary;Institute of Genetics, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári krt. 62, H-6726, Szeged, Hungary;AVIDIN Ltd., Szeged, Hungary;Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary;AVIDIN Ltd., Szeged, Hungary;Institute of Genetics, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári krt. 62, H-6726, Szeged, Hungary;Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary;Institute of Genetics, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári krt. 62, H-6726, Szeged, Hungary;Institute of Plant Biology, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary;

关键词: Hepatocellular carcinoma;    Lipid droplet;    Heat-shock proteins;    Protein disulfide isomerase;    Reactive oxigen species;   

DOI  :  10.1186/1476-511X-12-175

 received in 2013-11-12, accepted in 2013-11-15,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundHepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and it has limited treatment options.ResultsIn 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.ConclusionThese results imply that these amino-trifluoro-phthalimide analogs could serve potent clinical candidates against HCC alone or in combination with dietary polyunsaturated fatty acids.

【 授权许可】

Unknown   
© Nagy et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.