Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells.
Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells.
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DOI：
10.1186/1476-511x-9-56
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发表时间：
2010-06-02
影响因子：
4.5
通讯作者：
Kitajka K
中科院分区：
文献类型：
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作者：
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
胞质脂滴是真核细胞中常见的内含物。合成了具有抗癌活性的沙利度胺类似物（2，6-二烷基苯基-4/5-氨基取代-5，6，7-三氟邻苯二甲酰亚胺）。在不同的细胞系中检测到细胞毒性，包括黑色素瘤、白血病、肝细胞癌、胶质母细胞瘤。合成的类似物对成年动物是无毒的，高达1克/公斤，但在微摩尔浓度下对斑马鱼胚胎具有致畸性，在发育中的肌肉中存在缺陷。处理肿瘤细胞导致钙从内质网（ER）释放，诱导活性氧（ROS），ER应激和细胞死亡。抗氧化剂可以部分减少ROS的产生，而细胞内钙螯合剂几乎完全减少ROS的产生。外源性二十二碳六烯酸或二十碳五烯酸诱导钙释放和活性氧产生，并协同类似物在体外，而油酸没有这样的效果。基因表达分析证实了ER应激介导的凋亡途径组分的诱导，如GADD 153、ATF 3、Luman/CREB 3和ER相关降解相关的HERPUD 1基因。肿瘤抑制因子P53、LATS 2和ING 3在药物处理后也在各种细胞系中上调。氨基邻苯二甲酰亚胺下调了与肿瘤转移和血管生成有关的CCL 2的表达。由于抗癌、抗血管生成作用和免疫调节药物（包括沙利度胺类似物）的广泛适用性，该家族的脂滴结合成员可能通过影响ER膜完整性和ER稳态的扰动而代表一类新的药物。
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. 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. 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.