A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth
A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth
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DOI：
10.1016/s1535-6108(02)00082-x
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发表时间：
2002-07-01
期刊：
影响因子：
50.3
通讯作者：
Leder, P
中科院分区：
文献类型：
--
作者：
Fantin, VR;Berardi, MJ;Leder, P
肿瘤的发生是影响多种相互协作的代谢途径的事件的结果。为了评估它们在这一过程中的作用，我们利用基于细胞的分析进行了高通量的化学文库筛选。在这样做的过程中，我们鉴定了F16，一种选择性地抑制乳腺上皮细胞、neu过表达细胞以及各种小鼠乳腺肿瘤和人乳腺癌细胞系的增殖的小分子。F16属于具有离域正电荷的一组结构相似的分子。在膜电位的驱动下，这种化合物积聚在反应细胞的线粒体中，它损害了细胞的功能完整性。线粒体超极化是许多肿瘤细胞系的共同特征，解释了这种新型离域亲脂阳离子的广泛作用光谱。
Tumorigenesis results from events that impinge on a variety of collaborating metabolic pathways. To assess their role in this process, we utilized a cell-based assay to perform a high-throughput, chemical library screen. In so doing, we identified F16, a small molecule that selectively inhibits proliferation of mammary epithelial, neu-overexpressing cells, as well as a variety of mouse mammary tumor and human breast cancer cell lines. F16 belongs to a group of structurally similar molecules with a delocalized positive charge. The compound is accumulated in mitochondria of responsive cells, driven by the membrane potential, and it compromises their functional integrity. Mitochondrial hyperpolarization is a shared feature of many tumor cell lines, explaining the broad action spectrum of this novel delocalized lipophilic cation.