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


RESULTS
Cytotoxicity 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.


CONCLUSIONS
Because 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.
Puskás
László G
LG
Avidin Biotechnology, Közép fasor 52, Szeged H-6726, Hungary. laszlo@avidinbiotech.com
Fehér
Liliána Z
LZ
Vizler
Csaba
C
Ayaydin
Ferhan
F
Rásó
Erzsébet
E
Molnár
Eszter
E
Magyary
István
I
Kanizsai
Iván
I
Gyuris
Márió
M
Madácsi
Ramóna
R
Fábián
Gabriella
G
Farkas
Klaudia
K
Hegyi
Péter
P
Baska
Ferenc
F
Ozsvári
Béla
B
Kitajka
Klára
K
D000818:Animals; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004625:Embryo, Nonmammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006706:Homeostasis; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology*; D015027:Zebrafish
D005231:Fatty Acids, Unsaturated; D013792:Thalidomide