Involvement of lipid rafts in the localization and dysfunction effect of the antitumor ether phospholipid edelfosine in mitochondria.
Involvement of lipid rafts in the localization and dysfunction effect of the antitumor ether phospholipid edelfosine in mitochondria.
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DOI：
10.1038/cddis.2011.41
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发表时间：
2011-05-19
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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脂质筏和线粒体是肿瘤治疗中有希望的靶点。合成的抗肿瘤烷基溶血磷脂类似物edelfosine（1-O-十八烷基-2-O-甲基-rac-甘油-3-磷酸胆碱）已被报道靶向脂筏。在这里，我们已经发现，edelfosine诱导的线粒体膜电位和细胞凋亡在人宫颈癌HeLa细胞的损失，这两个反应被废除Bcl-xL过表达。我们合成了一些新的荧光edelfosine类似物，保留了母体药物的促凋亡活性，并与HeLa细胞中的线粒体共定位。在离体线粒体中，依地福新诱导肿胀，表明线粒体膜通透性增加。这种线粒体肿胀是独立的活性氧的产生。结构相关的无活性类似物不能促进线粒体肿胀，突出了依地福新分子结构在其对线粒体的作用中的重要性。筏破坏抑制线粒体定位的药物在细胞和edelfosine诱导的肿胀在孤立的线粒体。Edelfosine促进了脂筏从质膜到线粒体的再分配，表明质膜和线粒体之间存在脂筏介导的联系。我们的数据表明，依地福新与线粒体的直接相互作用最终导致线粒体功能障碍和细胞凋亡。这些观察揭示了癌症化疗的新框架，该框架涉及抗肿瘤药物作用机制中脂筏和线粒体之间的联系，从而为癌症治疗开辟了新途径。
Lipid rafts and mitochondria are promising targets in cancer therapy. The synthetic antitumor alkyl-lysophospholipid analog edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) has been reported to target lipid rafts. Here, we have found that edelfosine induced loss of mitochondrial membrane potential and apoptosis in human cervical carcinoma HeLa cells, both responses being abrogated by Bcl-xL overexpression. We synthesized a number of new fluorescent edelfosine analogs, which preserved the proapoptotic activity of the parent drug, and colocalized with mitochondria in HeLa cells. Edelfosine induced swelling in isolated mitochondria, indicating an increase in mitochondrial membrane permeability. This mitochondrial swelling was independent of reactive oxygen species generation. A structurally related inactive analog was unable to promote mitochondrial swelling, highlighting the importance of edelfosine molecular structure in its effect on mitochondria. Raft disruption inhibited mitochondrial localization of the drug in cells and edelfosine-induced swelling in isolated mitochondria. Edelfosine promoted a redistribution of lipid rafts from the plasma membrane to mitochondria, suggesting a raft-mediated link between plasma membrane and mitochondria. Our data suggest that direct interaction of edelfosine with mitochondria eventually leads to mitochondrial dysfunction and apoptosis. These observations unveil a new framework in cancer chemotherapy that involves a link between lipid rafts and mitochondria in the mechanism of action of an antitumor drug, thus opening new avenues for cancer treatment.
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DOI：
10.1084/jem.20040213
发表时间：
2004-08-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gajate C;Del Canto-Jañez E;Acuña AU;Amat-Guerri F;Geijo E;Santos-Beneit AM;Veldman RJ;Mollinedo F
通讯作者：
Mollinedo F
DOI：
10.1016/j.bbrc.2009.01.147
发表时间：
2009-03-20
影响因子：
3.1
作者：
Gajate, Consuelo;Gonzalez-Camacho, Fernando;Mollinedo, Faustino
通讯作者：
Mollinedo, Faustino
影响因子：
12.4
作者：
Ciarlo, L.;Manganelli, V.;Sorice, M.
通讯作者：
Sorice, M.
影响因子：
12.4
作者：
Garofalo, T;Giammarioli, A;Sorice, M
通讯作者：
Sorice, M
影响因子：
20.3
作者：
Gajate, C;Mollinedo, F
通讯作者：
Mollinedo, F