Journal Article

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

Nagy, Lajos I, Deák, Ferenc, Puskás, László G, Madácsi, Ramóna, Mátés, Lajos, Kiss, Ibolya, Ózsvári, Béla, Kitajka, Klára, Hackler, László, Molnár, Eszter, Vizler, Csaba, Fehér, Liliána Z, Ayaydin, Ferhan, Kanizsai, Iván, Marton, Annamária, Fábián, Gabriella

2013

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Affinity chromatography / Analysis / Animals / Antineoplastic Agents - pharmacokinetics / Antineoplastic Agents - pharmacology / Apoptosis / Biomedical and Life Sciences / Cancer therapies / Carcinoma, Hepatocellular - chemically induced / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / Care and treatment / Cell adhesion & migration / Cell culture / Cell death / Cell Line, Tumor / Cell Movement - drug effects / Cell Proliferation - drug effects / Chaperonin 60 - genetics / Chaperonin 60 - metabolism / Clinical Nutrition / Diagnosis / Diethylnitrosamine / Endoplasmic reticulum / Endoplasmic Reticulum - drug effects / Endoplasmic Reticulum - metabolism / Endoplasmic Reticulum Stress - drug effects / Endoplasmic Reticulum Stress - genetics / Female / Gene Expression / Health aspects / Heat shock proteins / Hepatocytes - drug effects / Hepatocytes - metabolism / Hepatocytes - pathology / Hepatoma / Homeostasis / HSP70 Heat-Shock Proteins - genetics / HSP70 Heat-Shock Proteins - metabolism / HSP90 Heat-Shock Proteins - genetics / HSP90 Heat-Shock Proteins - metabolism / Humans / Lasers / Life Sciences / Lipidology / Lipids / Lipids - chemistry / Liver / Liver - drug effects / Liver - metabolism / Liver - pathology / Liver cancer / Liver Neoplasms - chemically induced / Liver Neoplasms - drug therapy / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Medical Biochemistry / Mice / Mice, Transgenic / Mitochondrial Proteins - genetics / Mitochondrial Proteins - metabolism / Mortality / Risk factors / Rodents / Statistical analysis / Stress / Studies / Thalidomide / Thalidomide - analogs & derivatives / Thalidomide - pharmacokinetics / Thalidomide - pharmacology / Tumor Burden - drug effects / Tumors / Unsaturated fatty acids