Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells

Lipids in Health and Disease

Research

Gabriella Fábián¹  Eszter Molnár²  Márió Gyuris³  Béla Ózsvári³  Liliána Z Fehér³  Iván Kanizsai³  Ramóna Madácsi³  László G Puskás⁴  Klára Kitajka⁵  István Magyary⁶  Ferhan Ayaydin⁷  Ferenc Baska⁸  Klaudia Farkas⁹  Péter Hegyi⁹  Csaba Vizler^1,10  Erzsébet Rásó^1,11 

[1] Avicor Ltd., Közép fasor 52., H-6726, Szeged, Hungary;Avicor Ltd., Közép fasor 52., H-6726, Szeged, Hungary;Laboratory of Functional Genomics, Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726, Szeged, Hungary;Avidin Biotechnology, Közép fasor 52., H-6726, Szeged, Hungary;Avidin Biotechnology, Közép fasor 52., H-6726, Szeged, Hungary;Avicor Ltd., Közép fasor 52., H-6726, Szeged, Hungary;Laboratory of Functional Genomics, Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726, Szeged, Hungary;Avidin Biotechnology, Közép fasor 52., H-6726, Szeged, Hungary;Laboratory of Functional Genomics, Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726, Szeged, Hungary;Biotecont Ltd., 1/1. Finn u., H-7630, Pécs, Hungary;Cellular Imaging Laboratory, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726, Szeged, Hungary;Faculty of Veterinary Science, Szent István University, István u. 2., H-1078, Budapest, Hungary;First Department of Medicine, University of Szeged, Korányi fasor 8-10., H-6720, Szeged, Hungary;Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62., H-6726, Szeged, Hungary;National Institute of Oncology, Ráth György u. 7-9., H-1011, Budapest, Hungary;

关键词: Endoplasmic Reticulum Stress;    Thalidomide;    HT168 Cell;    K562 Cell;    Lenalidomide;   

DOI  :  10.1186/1476-511X-9-56

 received in 2010-04-27, accepted in 2010-06-02,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundCytoplasmic lipid-droplets are common inclusions of eukaryotic cells. Lipid-droplet binding thalidomide analogs (2,6-dialkylphenyl-4/5-amino-substituted-5,6,7-trifluorophthalimides) with potent anticancer activities were synthesized.ResultsCytotoxicity was detected in different cell lines including melanoma, leukemia, hepatocellular carcinoma, glioblastoma at micromolar concentrations. The synthesized analogs are non-toxic to adult animals up to 1 g/kg but are teratogenic to zebrafish embryos at micromolar concentrations with defects in the developing muscle. Treatment of tumor cells resulted in calcium release from the endoplasmic reticulum (ER), induction of reactive oxygen species (ROS), ER stress and cell death. Antioxidants could partially, while an intracellular calcium chelator almost completely diminish ROS production. Exogenous docosahexaenoic acid or eicosapentaenoic acid induced calcium release and ROS generation, and synergized with the analogs in vitro, while oleic acid had no such an effect. Gene expression analysis confirmed the induction of ER stress-mediated apoptosis pathway components, such as GADD153, ATF3, Luman/CREB3 and the ER-associated degradation-related HERPUD1 genes. Tumor suppressors, P53, LATS2 and ING3 were also up-regulated in various cell lines after drug treatment. Amino-phthalimides down-regulated the expression of CCL2, which is implicated in tumor metastasis and angiogenesis.ConclusionsBecause of the anticancer, anti-angiogenic action and the wide range of applicability of the immunomodulatory drugs, including thalidomide analogs, lipid droplet-binding members of this family could represent a new class of agents by affecting ER-membrane integrity and perturbations of ER homeostasis.

【 授权许可】

CC BY   
© Puskás et al; licensee BioMed Central Ltd. 2010