Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
Curr Mol Med. 2011 Aug;11(6):503-11. doi: 10.2174/156652411796268740.
In this study, we investigated whether DHA, a nutritionally important n-3 unsaturated fatty acid, modulated the sensitivity of brain tumor cells to the anticancer drug, etoposide (VP16). Medulloblastoma (MB) cell lines, Daoy and D283, and glioblastoma (GBM) cell lines, U138 and U87, were exposed to DHA or VP16 alone or in combination. The effects on cell proliferation and the induction of apoptosis were determined by using MTS and Hoechest 33342/PI double staining. U87 and U138 cells were found to be insensitive to the addition of DHA and VP16, whereas the two MB cell lines showed high sensitivity. DHA or VP16 alone showed little effect on cell proliferation or death in either the MB or GBM cell lines, but pretreatment with DHA enhanced the responsiveness to VP16 in the MB cell lines. To understand the mechanisms of combined DHA and VP16 on MB cells, pathway specific oligo array analyses were performed to dissect possible signaling pathways involved. The addition of DHA and VP16, in comparison to VP16 added alone, resulted in marked suppression in the expression of several genes involved in DNA damage repair, cell proliferation, survival, invasion, and angiogenesis, including PRKDC, Survivin, PIK3R1, MAPK14, NFκB1, NFκBIA, BCL2, CD44, and MAT1. These results suggest (1) that the effects of DHA and VP16 in brain tumor cells are mediated in part by the down regulation of events involved in DNA repair and the PI3K/MAPK signaling pathways and (2) that brain tumors genotypically mimicked by MB cells may benefit from therapies combining DHA with VP16.
在这项研究中，我们研究了二十二碳六烯酸（DHA）是否作为一种营养上重要的 n-3 不饱和脂肪酸，调节脑瘤细胞对抗癌药物依托泊苷（VP16）的敏感性。单独或联合暴露于 DHA 或 VP16 的髓母细胞瘤（MB）细胞系 Daoy 和 D283 以及神经胶质瘤（GBM）细胞系 U138 和 U87，通过 MTS 和 Hoechest 33342/PI 双重染色确定对细胞增殖和诱导凋亡的影响。U87 和 U138 细胞对添加 DHA 和 VP16 不敏感，而这两种 MB 细胞系表现出高敏感性。DHA 或 VP16 单独对 MB 或 GBM 细胞系的细胞增殖或死亡几乎没有影响，但 DHA 的预处理增强了 MB 细胞系对 VP16 的反应性。为了了解 DHA 和 VP16 联合对 MB 细胞的作用机制，进行了途径特异性寡核苷酸阵列分析，以剖析可能涉及的信号通路。与单独添加 VP16 相比，添加 DHA 和 VP16 导致与 DNA 损伤修复、细胞增殖、存活、侵袭和血管生成相关的几个基因的表达明显受到抑制，包括 PRKDC、Survivin、PIK3R1、MAPK14、NFκB1、NFκBIA、BCL2、CD44 和 MAT1。这些结果表明：（1）DHA 和 VP16 在脑瘤细胞中的作用部分是通过下调与 DNA 修复和 PI3K/MAPK 信号通路相关的事件介导的；（2）与 MB 细胞模拟的脑肿瘤基因型可能受益于将 DHA 与 VP16 联合治疗的疗法。
