Culver Carolyn A, Michalowski Susan M, Maia Rita C, Laster Scott M
Department of Microbiology, North Carolina State University Raleigh, NC 27695, USA.
Life Sci. 2005 Sep 23;77(19):2457-70. doi: 10.1016/j.lfs.2005.03.023.
Nordihydroguaiaretic acid (NDGA) is a plant lignan produced by Larrea tridentata, the creosote bush of the American southwest. In this report we examine the mechanism underlying the ability of NDGA to inhibit TNF-induced apoptosis. Our results show that NDGA blocks many key indicators of apoptosis. Caspase cleavage, mitochondrial inactivation, externalization of phosphatidyl serine, and (51)Cr-release were all blocked by low micromolar concentrations of NDGA. NDGA also inhibited the cPLA(2)-dependent release of (3)H-arachidonic acid. We investigated this activity and found that NDGA prevented the rise in intracellular calcium necessary for the apoptotic activation of cPLA(2). On the other hand, NDGA did not interfere with the TNF-induced phosphorylation of cPLA(2), indicating that NDGA does not block all TNF-dependent signaling. Finally, we asked whether the anti-apoptotic effect of NDGA could be attributed to its anti-oxidant activity. Comparison with the effects of butylated hydroxyanisole (BHA) did not completely support this hypothesis. While BHA strongly inhibited caspase activation and partially blocked the release of (51)Cr, it was unable to significantly block the calcium response or the release of (3)H-arachidonic acid associated with TNF-induced apoptosis. The anti-oxidant activity of NDGA may, therefore, explain some but not all of its anti-apoptotic activity.
去甲二氢愈创木酸（NDGA）是一种由美国西南部的杂酚油灌木三齿拉瑞阿（Larrea tridentata）产生的植物木脂素。在本报告中，我们研究了NDGA抑制肿瘤坏死因子（TNF）诱导的细胞凋亡的机制。我们的结果表明，NDGA阻断了细胞凋亡的许多关键指标。半胱天冬酶裂解、线粒体失活、磷脂酰丝氨酸外化和（51）铬释放均被低微摩尔浓度的NDGA阻断。NDGA还抑制了依赖于胞质磷脂酶A2（cPLA2）的（3）H-花生四烯酸释放。我们研究了这种活性，发现NDGA阻止了cPLA2凋亡激活所必需的细胞内钙升高。另一方面，NDGA不干扰TNF诱导的cPLA2磷酸化，表明NDGA并不阻断所有TNF依赖的信号传导。最后，我们询问NDGA的抗凋亡作用是否可归因于其抗氧化活性。与丁基羟基茴香醚（BHA）的作用比较并不完全支持这一假设。虽然BHA强烈抑制半胱天冬酶激活并部分阻断（51）铬释放，但它无法显著阻断与TNF诱导的细胞凋亡相关的钙反应或（3）H-花生四烯酸释放。因此，NDGA的抗氧化活性可能解释了其部分而非全部的抗凋亡活性。
