Escribá P V, Sastre M, García-Sevilla J A
Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma de Mallorca, Spain.
Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7595-9. doi: 10.1073/pnas.92.16.7595.
Albeit anthracyclines are widely used in the treatment of solid tumors and leukemias, their mechanism of action has not been elucidated. The present study gives relevant information about the role of nonlamellar membrane structures in signaling pathways, which could explain how anthracyclines can exert their cytocidal action without entering the cell [Tritton, T. R. & Yee, G. (1982) Science 217, 248-250]. The anthracycline daunomycin reduced the formation of the nonlamellar hexagonal (HII) phase (i.e., the hexagonal phase propensity), stabilizing the bilayer structure of the plasma membrane by a direct interaction with membrane phospholipids. As a consequence, various cellular events involved in signal transduction, such as membrane fusion and membrane association of peripheral proteins [e.g., guanine nucleotide-binding regulatory proteins (G proteins and protein kinase C-alpha beta)], where nonlamellar structures (negative intrinsic monolayer curvature strain) are required, were altered by the presence of daunomycin. Functionally, daunomycin also impaired the expression of the high-affinity state of a G protein-coupled receptor (ternary complex for the alpha 2-adrenergic receptor) due to G-protein dissociation from the plasma membrane. In vivo, daunomycin also decreased the levels of membrane-associated G proteins and protein kinase C-alpha beta in the heart. The occurrence of such nonlamellar structures favors the association of these peripheral proteins with the plasma membrane and prevents daunomycin-induced dissociation. These results reveal an important role of the lipid component of the cell membrane in signal transduction and its alteration by anthracyclines.
尽管蒽环类药物广泛用于实体瘤和白血病的治疗，但其作用机制尚未阐明。本研究提供了有关非片层膜结构在信号通路中作用的相关信息，这可以解释蒽环类药物如何在不进入细胞的情况下发挥其杀细胞作用[特里顿，T. R. & 叶，G.（1982年）《科学》217, 248 - 250]。蒽环类药物柔红霉素减少了非片层六方（HII）相的形成（即六方相倾向），通过与膜磷脂直接相互作用稳定了质膜的双层结构。结果，参与信号转导的各种细胞事件，如膜融合和外周蛋白的膜结合[例如鸟嘌呤核苷酸结合调节蛋白（G蛋白和蛋白激酶C-αβ）]，这些过程需要非片层结构（负的内在单层曲率应变），都因柔红霉素的存在而发生改变。在功能上，柔红霉素还由于G蛋白从质膜解离而损害了G蛋白偶联受体高亲和力状态（α2 - 肾上腺素能受体的三元复合物）的表达。在体内，柔红霉素还降低了心脏中膜相关G蛋白和蛋白激酶C-αβ的水平。这种非片层结构的出现有利于这些外周蛋白与质膜的结合，并防止柔红霉素诱导的解离。这些结果揭示了细胞膜脂质成分在信号转导中的重要作用以及蒽环类药物对其的改变。
