γ-linolenic acid and eicosapentaenoic acid induce modifications in mitochondrial metabolism, reactive oxygen species generation, lipid peroxidation and apoptosis in Walker 256 rat carcinosarcoma cells
γ-linolenic acid and eicosapentaenoic acid induce modifications in mitochondrial metabolism, reactive oxygen species generation, lipid peroxidation and apoptosis in Walker 256 rat carcinosarcoma cells
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DOI：
10.1016/s1388-1981(01)00136-6
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发表时间：
2001-10-31
影响因子：
4.8
通讯作者：
Schumacher, RI
中科院分区：
文献类型：
--
作者：
Colquhoun, A;Schumacher, RI
多不饱和脂肪酸伽马-亚麻酸(GLA)和二十碳五烯酸(EPA)对肿瘤细胞具有细胞毒性。GLA在体内抑制Walker 256肿瘤的生长，导致线粒体超微结构和细胞代谢的改变。本研究的目的是探讨脂肪酸抑制Walker 256肿瘤生长的机制。在受控的体外条件下，GLA和EPA在150微米的浓度下均可导致细胞增殖下降和凋亡指数增加。发现了活性氧(ROS)和过氧化脂质生成的增加，以及能量代谢的变化和以脂滴形式沉积的大量三酰甘油。线粒体呼吸链复合体I+III和IV活性明显降低，线粒体膜电位显著降低。尽管线粒体功能下降，但细胞内的ATP浓度保持在控制值的70%-80%，这可能部分是由于增加了对葡萄糖的利用来产生ATP。线粒体释放细胞色素c，半胱氨酸天冬氨酸氨基转移酶-3激活。原位DNA片段化显示了细胞群体中的许多凋亡事件。ROS和过氧化脂质诱导细胞凋亡的机制(S)尚不清楚，但GLA和EPA的作用可能涉及导致细胞色素c释放、caspase激活、线粒体膜电位丧失和DNA片段化的线粒体凋亡途径。(C)2001 Elsevier Science B.V.保留所有权利。
The polyunsaturated fatty acids gamma -linolenic acid (GLA) and eicosapentaenoic acid (EPA) are cytotoxic to tumour cells. GLA inhibits Walker 256 tumour growth in vivo, causing alterations in mitochondrial ultrastructure and cellular metabolism. The objective of the present study was to investigate the mechanisms behind fatty acid inhibition of Walker 256 tumour growth under controlled in vitro conditions, At a concentration of 150 muM, both GLA and EPA caused a decrease in cell proliferation and an increase in apoptotic index. Increases in reactive oxygen species (ROS) and lipid peroxide production were identified, as well as alterations in energy metabolism and the deposition of large amounts of triacylglycerol in the form of lipid droplets. Mitochondrial respiratory chain complexes I+III and IV had significantly decreased activity and mitochondrial membrane potential was greatly diminished. Intracellular ATP concentrations were maintained at 70-80% of control values despite the decreased mitochondrial function, which may be in part due to increased utilisation of glucose for ATP generation. Cytochrome c release from mitochondria was found, as was caspase-3-like activation. DNA fragmentation in situ revealed many apoptotic events within the cell population. The mechanism(s) by which ROS and lipid peroxides induce apoptosis remains unclear, but the effects of GLA and EPA appear to involve the mitochondrial pathway of apoptosis induction leading to cytochrome c release, caspase activation, loss of mitochondrial membrane potential and DNA fragmentation. (C) 2001 Elsevier Science B.V. All rights reserved.