Tronstad K J, Berge K, Dyroy E, Madsen L, Berge R K
Department of Clinical Biochemistry, University of Bergen, Haukeland Hospital, N-5021, Bergen, Norway.
Biochem Pharmacol. 2001 Mar 15;61(6):639-49. doi: 10.1016/s0006-2952(01)00525-1.
During aerobic metabolism, a small amount of partially reduced oxygen is produced, yielding reactive oxygen species (ROS). Peroxisomes and mitochondria are major contributors to cellular ROS production, which is normally balanced by consumption by antioxidants. The fatty acid analogue tetradecylthioacetic acid (TTA) promotes mitochondrial and peroxisomal proliferation, and may induce oxidative stress and change the growth potential of cancer cells. In the present study, we found that TTA reduced [(3)H]thymidine incorporation in the glioma cell lines BT4Cn (rat), D54Mg (human), and GaMg (human) in a dose- and time-dependent manner. The 50% inhibitory TTA doses were approximately 125 microM for BT4Cn and D54Mg cells and 40 microM for GaMg cells after 4 days. alpha-Tochopherol counteracted this inhibition in GaMg cells. TTA enhanced the oxidation of [1-(14)C]palmitic acid, which could be explained by stimulation of enzymes involved in peroxisomal (fatty acyl-CoA oxidase) and/or mitochondrial (carnitine palmitoyltransferase) fatty acid oxidation. The glutathione content and the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase were differentially affected. Increased malondialdehyde (MDA) production was seen in TTA-treated GaMg and D54Mg cells, but not in BT4Cn cells, in vitro. In BT4Cn tumor tissue from TTA-treated rats, MDA was increased while the alpha-tocopherol content tended to decrease. TTA increased the level of cytosolic cytochrome c in BT4Cn cells, which suggests induction of apoptotic cascades. Although several mechanisms are likely to be involved in the TTA-mediated effects on growth, we propose that modulation of cellular redox conditions caused by changes in fatty acid metabolism may be of vital importance.
在有氧代谢过程中，会产生少量部分还原的氧，进而产生活性氧（ROS）。过氧化物酶体和线粒体是细胞ROS产生的主要来源，而抗氧化剂的消耗通常可使ROS产生与消耗保持平衡。脂肪酸类似物十四烷基硫代乙酸（TTA）可促进线粒体和过氧化物酶体的增殖，并可能诱导氧化应激，改变癌细胞的生长潜能。在本研究中，我们发现TTA以剂量和时间依赖性方式降低了胶质瘤细胞系BT4Cn（大鼠）、D54Mg（人）和GaMg（人）中[³H]胸腺嘧啶核苷的掺入。4天后，BT4Cn和D54Mg细胞的TTA半数抑制剂量约为125μM，GaMg细胞为40μM。α-生育酚可抵消GaMg细胞中的这种抑制作用。TTA增强了[1-¹⁴C]棕榈酸的氧化，这可以通过刺激参与过氧化物酶体（脂肪酰辅酶A氧化酶）和/或线粒体（肉碱棕榈酰转移酶）脂肪酸氧化的酶来解释。谷胱甘肽含量以及谷胱甘肽过氧化物酶、谷胱甘肽还原酶和谷胱甘肽S-转移酶的活性受到不同程度的影响。在体外，TTA处理的GaMg和D54Mg细胞中丙二醛（MDA）产量增加，但BT4Cn细胞中未增加。在TTA处理大鼠的BT4Cn肿瘤组织中，MDA增加，而α-生育酚含量趋于降低。TTA增加了BT4Cn细胞中细胞色素c的胞质水平，这表明诱导了凋亡级联反应。尽管TTA对生长的影响可能涉及多种机制，但我们认为由脂肪酸代谢变化引起的细胞氧化还原状态的调节可能至关重要。
