Aranorosin and a novel derivative inhibit the anti-apoptotic functions regulated by Bcl-2
Aranorosin and a novel derivative inhibit the anti-apoptotic functions regulated by Bcl-2
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DOI：
10.1016/j.bbrc.2008.10.112
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发表时间：
2008-12-26
影响因子：
3.1
通讯作者：
Hara, Mitsunobu
中科院分区：
文献类型：
--
作者：
Nakashima, Takayuki;Tanaka, Rieko;Hara, Mitsunobu
Bcl-2是一种细胞内膜蛋白，其防止细胞响应于各种细胞死亡信号而经历凋亡。它负调节线粒体外膜透化，这是负责释放促凋亡因子和随后激活半胱天冬酶。一种微生物代谢产物aranorosin被鉴定为Bcl-2抗凋亡功能的抑制剂。以其结构为基础，合成了一种更有效的衍生物K 050。细胞凋亡可以诱导过度表达Bcl-2的细胞系，当细胞用抗Fas抗体除了K 050，在亚微摩尔浓度。此外，K 050抑制由Bcl-2调节的抗凋亡功能，导致Fas触发的线粒体跨膜电位丧失、caspase-9的激活和凋亡的形态学改变。抑制Bcl-2的细胞功能及其抗凋亡作用可能是有用的药理学作用。因此，一种新的aranorosin衍生物，K 050，可能是一种有效的治疗剂对Bcl-2过表达的人类恶性肿瘤。(C)2008年爱思唯尔公司版权所有
Bcl-2 is an intracellular membrane protein that prevents cells from undergoing apoptosis in response to various cell-death signals. It negatively regulates mitochondrial outer membrane permeabilization, which is responsible for the release of apoptogenic factors and the subsequent activation of caspases. A microbial metabolite, aranorosin, was identified as an inhibitor of the anti-apoptotic function of Bcl-2. Based oil its structure, a more potent derivative, K050, was synthesized. Apoptosis could be induced in a cell line that overexpressed Bcl-2 when cells were treated with an anti-Fas antibody in addition to K050, at sub-micromolar concentrations. Furthermore, K050 inhibited anti-apoptotic functions regulated by Bcl-2, resulting in a Fas-triggered mitochondrial transmembrane potential loss, the activation of caspase-9, and a morphological change to apoptosis. Inhibition of cell-based function of Bcl-2 and its antiapoptotic effects could serve as useful pharmacological effects. Thus, a novel aranorosin derivative, K050, could be a potent therapeutic agent against Bcl-2-overexpressing human malignancies. (C) 2008 Elsevier Inc. All rights reserved