Apoptolidin, a selective cytotoxic agent, is an inhibitor of F0F1-ATPase
Apoptolidin, a selective cytotoxic agent, is an inhibitor of F0F1-ATPase
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DOI：
10.1016/s1074-5521(00)00057-0
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发表时间：
2001-01-01
影响因子：
--
通讯作者：
Khosla, C
中科院分区：
文献类型：
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作者：
Salomon, AR;Voehringer, DW;Khosla, C
背景资料：Apoptolidin是一种大环内酯，最初基于其选择性杀死E1 A和E1 A/E1 B19 K转化的大鼠神经胶质细胞而不杀死未转化的神经胶质细胞的能力而鉴定。本研究的目的是确定这种新发现的天然产物的分子靶点，结果：我们的方法来揭示的作用机制的雷公藤甲素利用分子和细胞为基础的药理学试验以及结构之间的比较雷公藤甲素和其他大环聚酮与已知的作用机制。雷公藤甲素诱导的细胞杀伤是独立的p53状态，抑制BCL-2，并依赖于caspase-9的作用。在小鼠淋巴瘤细胞系中，在1 μ M雷公藤内酯醇存在下，PARP在6小时内被完全裂解。这些结果共同表明，雷公藤甲素可能靶向线粒体蛋白。与其他大环内酯类化合物的结构比较显示，雷公藤内酯苷配基与寡霉素（一种已知的线粒体F0 F1-ATP合酶抑制剂）之间存在显著的相似性。这种相似性的相关性是通过证明雷公藤甲素是完整酵母线粒体以及Triton X-100增溶的ATP酶制剂中F0 F1-ATP酶活性的有效抑制剂来建立的。雷公藤甲素的Ki为4-5 μ M。发现NCI-60细胞系组中雷公藤甲素的选择性与抑制真核线粒体F0 F1-ATP合酶的几种已知抗真菌天然产物的选择性良好相关。尽管线粒体F0 F1-ATP合酶的大环内酯类抑制剂如寡霉素、奥沙霉素和胞壁曲张菌素的抗真菌活性已被充分证明，它们对某些细胞类型的不寻常的选择性没有被广泛认识。最近发现的雷公藤甲素。随后证明它是线粒体FI，FI-ATP合酶的抑制剂，突出了这些天然产物作为小分子调节凋亡途径的潜在相关性。线粒体ATP合成酶抑制剂的选择性细胞毒性的机制基础进行了讨论。(C)2001爱思唯尔科技有限公司版权所有。
Background: Apoptolidin is a macrolide originally identified on the basis of its ability to selectively kill E1A and E1A/E1B19K transformed rat glial cells while not killing untransformed glial cells. The goal of this study was to identify the molecular target of this newly discovered natural product,Results: Our approach to uncovering the mechanism of action of apoptolidin utilized a combination of molecular and cell-based pharmacological assays as well as structural comparisons between apoptolidin and other macrocyclic polyketides with known mechanism of action. Cell killing induced by apoptolidin was independent of p53 status, inhibited by BCL-2, and dependent on the action of caspase-9. PARP was completely cleaved in the presence of 1 muM apoptolidin within 6 h in a mouse lymphoma cell line. Together these results suggested that apoptolidin might target a mitochondrial protein. Structural comparisons between apoptolidin and other macrolides revealed significant similarity between the apoptolidin aglycone and oligomycin, a known inhibitor of mitochondrial F0F1-ATP synthase. The relevance of this similarity was established by demonstrating that apoptolidin is a potent inhibitor of the F0F1-ATPase activity in intact yeast mitochondria as well as Triton X-100-solubilized ATPase preparations. The K-i For apoptolidin was 4-5 muM. The selectivity of apoptolidin in the NCI-60 cell line panel was found to correlate well with that of several known anti-fungal natural products that inhibit the eukaryotic mitochondrial F0F1-ATP synthase.Significance: Although the anti-fungal activities of macrolide inhibitors of the mitochondrial F0F1-ATP synthase such as oligomycin, ossamycin and cytovaricin are well-documented, their unusual selectivity toward certain cell types is not widely appreciated. The recent discovery of apoptolidin. followed by the demonstration that it is an inhibitor of the mitochondrial FI,FI-ATP synthase, highlights the potential relevance of these natural products as small molecules to modulate apoptotic pathways. The mechanistic basis for selective cytotoxicity of mitochondrial ATP synthase inhibitors is discussed. (C) 2001 Elsevier Science Ltd. All rights reserved.