Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines
Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines
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DOI：
10.3171/2014.10.jns14759
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发表时间：
2015-03-01
影响因子：
4.1
通讯作者：
Siddiqui, Rafat A.
中科院分区：
文献类型：
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作者：
Harvey, Kevin A.;Xu, Zhidong;Siddiqui, Rafat A.
目的：胶质母细胞瘤是一种快速浸润性肿瘤，尽管各种形式的积极治疗，但它总是重新出现。脑肿瘤通常用烷基化药物治疗，如洛莫司汀，这是一种化疗药物。然而，使用这些药物会产生严重的副作用。为了减少副作用，一种方法是将低剂量的化疗药物与其他无毒的抗癌药物结合使用。在这项研究中，使用胶质母细胞瘤细胞系，作者研究了洛莫司汀的抗癌作用，单独使用和与二十二碳六烯酸（DHA）联合使用，DHA是一种omega-3多不饱和脂肪酸，通常在大脑中丰富，以其抗癌潜力而闻名。方法采用3种人源性肿瘤细胞系（U87-MG、DB029和MHBT161）培养细胞，分别添加DHA或洛莫司汀，利用线粒体功能指标WST-1测定细胞的生长抑制潜能。人源性大脑皮层微血管内皮细胞作为正常表型对照。用气相色谱法分析DHA的细胞掺入。采用流式细胞术分析，量化DHA和/或洛莫司汀对诱导细胞凋亡和/或坏死的作用；随后，DHA和洛莫司汀对细胞周期进程的影响也被评估。Western blot分析证实了下游细胞靶点的作用。结果DHA （ED50 68.3 mu M）和洛莫司汀（ED50 68.1 mu M）均能抑制U87-MG的生长；然而，当U87-MG细胞被给予等摩尔剂量的每种化合物时，生长抑制作用增强，导致50 μ m的几乎完全生长抑制。
OBJECT Glioblastoma is a rapidly infiltrating tumor that consistently rematerializes despite various forms of aggressive treatment. Brain tumors are commonly treated with alkylating drugs, such as lomustine, which are chemotherapeutic agents. Use of these drugs, however, is associated with serious side effects. To reduce the side effects, one approach is to combine lower doses of chemotherapeutic drugs with other nontoxic anticancer agents. In this study, using glioblastoma cell lines, the authors investigated the anticancer effects of lomustine, alone and in combination with docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid normally abundant in the brain and known for its anticancer potential.METHODS Cells were cultured from 3 human-derived tumor cell lines (U87-MG, DB029, and MHBT161) and supplemented with either DHA or lomustine to determine the growth inhibitory potential using WST-1, a mitochondrial functional indicator. Human-derived cerebral cortex microvascular endothelial cells served as a normal phenotypic control. Cellular incorporation of DHA was analyzed by gas chromatography. Using flow cytometric analysis, the DHA and/or lomustine effect on induction of apoptosis and/or necrosis was quantified; subsequently, the DHA and lomustine effect on cell cycle progression was also assessed. Western blot analysis confirmed the role of downstream cellular targets.RESULTS U87-MG growth was inhibited with the supplementation of either DHA (ED50 68.3 mu M) or lomustine (ED50 68.1 mu M); however, growth inhibition was enhanced when U87-MG cells were administered equimolar doses of each compound, resulting in nearly total growth inhibition at 50 mu M. Gas chromatography analysis of the fatty acid profile in DHA-supplemented U87-MG cells resulted in a linear dose-dependent increase in DHA incorporation (