Selective inhibition of Δ-6 desaturase impedes intestinal tumorigenesis
Selective inhibition of Δ-6 desaturase impedes intestinal tumorigenesis
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DOI：
10.1016/s0304-3835(01)00715-7
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发表时间：
2002-01-25
期刊：
影响因子：
9.7
通讯作者：
Whelan, J
中科院分区：
文献类型：
--
作者：
Hansen-Petrik, MB;McEntee, MF;Whelan, J
花生四烯酸是一种重要的参与细胞信号传导的多不饱和脂肪酸。它主要来源于膳食中的亚油酸，其生物合成的限速步骤是通过δ -6去饱和酶使亚油酸初始去饱和。有证据表明，花生四烯酸的下游代谢产物，如前列腺素，与结直肠癌有关，但花生四烯酸的生物合成途径的参与尚未被研究。在本研究中，我们报道了一种新的选择性δ -6去饱和酶抑制剂SC-26196对两种体内肠癌模型的肿瘤发生的影响。SC-26196治疗后，Apc（Min/+）小鼠的肿瘤减少36-37%，移植HT-29人结肠癌细胞的裸鼠原发肿瘤大小减少35% （P < 0.05）。正如预期的那样，SC-26196处理显著提高了组织磷脂中的亚油酸水平，降低了花生四烯酸水平。同时给予花生四烯酸对Apc（Min/+）小鼠组织脂肪酸组成和肿瘤发生的影响均被消除，表明所观察到的影响是由于干扰了花生四烯酸的生物合成途径。(C) 2002爱思唯尔科学爱尔兰有限公司版权所有。
Arachidonic acid is an important polyunsaturated fatty acid involved in cell signaling. It is derived primarily from dietary linoleic acid, and the rate-limiting step in its biosynthesis is the initial desaturation of linoleic acid via Delta-6 desaturase. Evidence suggests that downstream metabolic products of arachidonic acid, e.g. prostaglandins, are involved in colorectal cancer, but involvement of the biosynthetic pathway of arachidonic acid has not been previously investigated. In the present study, we report the effects of a novel selective, Delta-6 desaturase inhibitor, SC-26196, on tumorigenesis in two in vivo models of intestinal cancer. SC-26196 treatment resulted in 36-37% fewer tumors in Apc(Min/+) mice and 35% decrease in primary tumor size in nude mice bearing HT-29 human colon cancer cell xenografts (P < 0.05). As expected, SC-26196 treatment resulted in significantly higher linoleic acid levels in tissue phospholipids and lower levels of arachidonic acid. The effects on both tissue fatty acid composition and tumorigenesis in Apc(Min/+) mice were abrogated by concomitant treatment with dietary arachidonic acid, indicating that the observed effects were due to interference with the biosynthetic pathway of arachidonic acid. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.