Gajate Consuelo, Mollinedo Faustino
Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSICUniversidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
Anticancer Agents Med Chem. 2014 May;14(4):509-27. doi: 10.2174/1871520614666140309222259.
The so-called alkylphospholipid analogs (APLs) constitute a family of synthetic antitumor compounds that target cell membranes. The ether phospholipid edelfosine has been considered the long-standing prototype of these antitumor agents and promotes apoptosis in tumor cells by a rather selective way, while sparing normal cells. Increasing evidence suggests that edelfosine-induced apoptosis involves a number of subcellular structures in tumor cells, including plasma membrane lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine has been shown to accumulate in plasma membrane lipid rafts, ER and mitochondria in different tumor cells in a cell type-dependent way. Edelfosine induces apoptosis in several hematopoietic cancer cells by recruiting death receptor and downstream apoptotic signaling molecules into lipid rafts and displacing survival signaling molecules from these membrane domains. However, in vitro and in vivo evidences suggest that edelfosine-induced apoptosis in solid tumor cells is mediated through an ER stress response. Both raft- and ER-mediated proapoptotic responses require a mitochondrial-related step to eventually promote cell death, and overexpression of Bcl-2 or Bcl-xL prevents edelfosine-induced apoptosis. Edelfosine can also interact with mitochondria leading to an increase in mitochondrial membrane permeability and loss of mitochondrial membrane potential. Edelfosine treatment also induced a redistribution of lipid rafts from the plasma membrane to mitochondria, suggesting a raft-mediated link between plasma membrane and mitochondria. The involvement of lipid rafts, ER and mitochondria in the apoptotic response induced by edelfosine may provide new avenues for targeting cancer cells as well as new opportunities for cancer therapy.
所谓的烷基磷脂类似物（APLs）构成了一类靶向细胞膜的合成抗肿瘤化合物。醚磷脂依地福新一直被视为这些抗肿瘤药物的长期原型，它以一种相当有选择性的方式促进肿瘤细胞凋亡，同时使正常细胞免受影响。越来越多的证据表明，依地福新诱导的凋亡涉及肿瘤细胞中的许多亚细胞结构，包括质膜脂筏、内质网（ER）和线粒体。已证明依地福新以细胞类型依赖的方式在不同肿瘤细胞的质膜脂筏、内质网和线粒体中积累。依地福新通过将死亡受体和下游凋亡信号分子募集到脂筏中，并将存活信号分子从这些膜结构域中置换出来，从而诱导多种造血癌细胞凋亡。然而，体外和体内证据表明，依地福新在实体瘤细胞中诱导的凋亡是通过内质网应激反应介导的。脂筏和内质网介导的促凋亡反应都需要一个与线粒体相关的步骤来最终促进细胞死亡，并且Bcl-2或Bcl-xL的过表达可阻止依地福新诱导的凋亡。依地福新还可与线粒体相互作用，导致线粒体膜通透性增加和线粒体膜电位丧失。依地福新处理还诱导脂筏从质膜重新分布到线粒体，表明质膜和线粒体之间存在脂筏介导的联系。脂筏、内质网和线粒体参与依地福新诱导的凋亡反应可能为靶向癌细胞提供新途径，也为癌症治疗提供新机会。
