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

Abstract

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.

Impact of contrasting fish oil concentrations in the diet on ovine embryo development <i>in vivo</i> and of corresponding diet-specific derivative sera during <i>in vitro</i> culture

“…In the same vein, Puskas et al (2010) demonstrated that EPA and DHA but not monounsaturated oleic acid synergised effectively with lipid-binding thalidomide analogues to induce oxidative stress in cancer cells. Albeit that such strategies aim to expose cancer cells to lethal antitumorigenic consequences, they also underline the capacity of PUFAs to exert dramatically different influences in accordance with the extent to which they are either protected from or are a focus for oxidative damage.…”

Characterization of a new class of blue-fluorescent lipid droplet markers for live-cell imaging in plants

“…In our earlier study, we have discovered in-house synthesized thalidomide analogs localizing to lipid droplets on human cancer cells (Puskás et al, 2010). Being blue fluorescent and plasma membrane permeable, these dyes are attractive candidates as fluorescent reporters for Lipid droplet (LD) studies in plant cells.…”

“…Moreover, biocompatibility and toxicity of these chemicals may also be different for plant cells. In addition to Ac-202 and Ac-1041 chemicals (Puskás et al, 2010), we have also included Ac-201 (a positional isomer of Ac-202) to test suitability of these chemicals as LD probes in plant cells. Using confocal laser scanning microscopy and fine rice suspension cultures (Oryza sativa L. japonica cv.…”

“…2,6-diisopropylphenyl-4/5-amino-substituted-4/5,6,7-trifluorophthalimides (AC-201: 4-ethlyamino-; AC-202: 5-ethyl-; AC-1041: 4-morpholine-) were synthesized as described previously (Puskás et al, 2010). Unless specified all chemicals were purchased from Sigma (Sigma, St. Louis,.…”

Talidomid analógok hatásának vizsgálata jelölésmentes szűrőrendszeren és a hepatocelluláris karcinóma egér modelljén

“…A lipid cseppecskék az endoplazmatikus retikulumban alakulnak ki. Az azokhoz kötődő kismolekulák pedig képesek befolyásolni illetve megváltoztatni a lipid cseppecskékhez köthető homeosztázist és az endoplazmatikus retikulum stresszen keresztül beindítani az apoptózist [82].…”