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

Lszlá G. Pusks, Lilina Z. Fehér, C. Vízler, F. Ayaydin, Erzsébet Rsá, Eszter Molnr, Istvn Magyary, Ivn Kanizsai, Mriá Gyuris, Ramána Madcsi, Gabriella Fbin, Klaudia Farkas, P. Hegyi, F. Baska, Béla Zsvri, K. Kitajka

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article number56
JournalLipids in Health and Disease
Volume9
DOIs
Publication statusPublished - 2010

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Thalidomide
Oxidative stress
Unsaturated Fatty Acids
Endoplasmic Reticulum
Tumors
Reactive Oxygen Species
Oxidative Stress
Endoplasmic Reticulum Stress
Cells
Lipids
Phthalimides
Endoplasmic Reticulum-Associated Degradation
Calcium
Drug therapy
Cell Line
Neoplasms
Eicosapentaenoic Acid
Docosahexaenoic Acids
Eukaryotic Cells
Zebrafish

ASJC Scopus subject areas

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

Cite this

Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells. / Pusks, Lszlá G.; Fehér, Lilina Z.; Vízler, C.; Ayaydin, F.; Rsá, Erzsébet; Molnr, Eszter; Magyary, Istvn; Kanizsai, Ivn; Gyuris, Mriá; Madcsi, Ramána; Fbin, Gabriella; Farkas, Klaudia; Hegyi, P.; Baska, F.; Zsvri, Béla; Kitajka, K.

In: Lipids in Health and Disease, Vol. 9, 56, 2010.

Research output: Contribution to journalArticle

Pusks, Lszlá G. ; Fehér, Lilina Z. ; Vízler, C. ; Ayaydin, F. ; Rsá, Erzsébet ; Molnr, Eszter ; Magyary, Istvn ; Kanizsai, Ivn ; Gyuris, Mriá ; Madcsi, Ramána ; Fbin, Gabriella ; Farkas, Klaudia ; Hegyi, P. ; Baska, F. ; Zsvri, Béla ; Kitajka, K. / Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells. In: Lipids in Health and Disease. 2010 ; Vol. 9.
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abstract = "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.",
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AU - Pusks, Lszlá G.

AU - Fehér, Lilina Z.

AU - Vízler, C.

AU - Ayaydin, F.

AU - Rsá, Erzsébet

AU - Molnr, Eszter

AU - Magyary, Istvn

AU - Kanizsai, Ivn

AU - Gyuris, Mriá

AU - Madcsi, Ramána

AU - Fbin, Gabriella

AU - Farkas, Klaudia

AU - Hegyi, P.

AU - Baska, F.

AU - Zsvri, Béla

AU - Kitajka, K.

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

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