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

Puskás LG, Fehér LZ, Vizler C, Ayaydin F, Rásó E, Molnár E, Magyary I, Kanizsai I, Gyuris M, Madácsi R, Fábián G, Farkas K, Hegyi P, Baska F, Ozsvári B, Kitajka K - Lipids Health Dis (2010)

Bottom Line: Treatment of tumor cells resulted in calcium release from the endoplasmic reticulum (ER), induction of reactive oxygen species (ROS), ER stress and cell death.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Avidin Biotechnology, Közép fasor 52, Szeged H-6726, Hungary. laszlo@avidinbiotech.com

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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Related in: MedlinePlus

Cytotoxic activity of 10 μM AC-1041 on human erythroleukemia cells. Pictures were recorded from the same area after 1 h and 24 h treatment. Cont: control cell lines treated with vehicle (0.1% DMSO). Cell divisions between 4 h-24 h are labeled with circles.
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Figure 3: Cytotoxic activity of 10 μM AC-1041 on human erythroleukemia cells. Pictures were recorded from the same area after 1 h and 24 h treatment. Cont: control cell lines treated with vehicle (0.1% DMSO). Cell divisions between 4 h-24 h are labeled with circles.

Mentions: Amino-trifluoro-phthalimides exerted potent anticancer activities in vitro. Cytotoxicity was evident after 4-16 h exposure depending on the cell type (data not shown). In human erythroleukemia cells (K562), which showed significant resistance against several thalidomide analogs [15], amino-trifluoro-phthalimides were effective below 10 μM concentration (for AC-1041 see Fig. 3).


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

Puskás LG, Fehér LZ, Vizler C, Ayaydin F, Rásó E, Molnár E, Magyary I, Kanizsai I, Gyuris M, Madácsi R, Fábián G, Farkas K, Hegyi P, Baska F, Ozsvári B, Kitajka K - Lipids Health Dis (2010)

Cytotoxic activity of 10 μM AC-1041 on human erythroleukemia cells. Pictures were recorded from the same area after 1 h and 24 h treatment. Cont: control cell lines treated with vehicle (0.1% DMSO). Cell divisions between 4 h-24 h are labeled with circles.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902471&req=5

Figure 3: Cytotoxic activity of 10 μM AC-1041 on human erythroleukemia cells. Pictures were recorded from the same area after 1 h and 24 h treatment. Cont: control cell lines treated with vehicle (0.1% DMSO). Cell divisions between 4 h-24 h are labeled with circles.
Mentions: Amino-trifluoro-phthalimides exerted potent anticancer activities in vitro. Cytotoxicity was evident after 4-16 h exposure depending on the cell type (data not shown). In human erythroleukemia cells (K562), which showed significant resistance against several thalidomide analogs [15], amino-trifluoro-phthalimides were effective below 10 μM concentration (for AC-1041 see Fig. 3).

Bottom Line: Treatment of tumor cells resulted in calcium release from the endoplasmic reticulum (ER), induction of reactive oxygen species (ROS), ER stress and cell death.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Avidin Biotechnology, Közép fasor 52, Szeged H-6726, Hungary. laszlo@avidinbiotech.com

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.

Show MeSH
Related in: MedlinePlus