Department of Biophysics and Cell Biology, University of Debrecen, Nagyerdei krt. 98, Debrecen 4032, Hungary.
Mar Drugs. 2013 Dec 2;11(12):4858-75. doi: 10.3390/md11124858.
The mechanism of action of elisidepsin (PM02734, Irvalec®) is assumed to involve membrane permeabilization via attacking lipid rafts and hydroxylated lipids. Here we investigate the role of hypoxia in the mechanism of action of elisidepsin. Culturing under hypoxic conditions increased the half-maximal inhibitory concentration and decreased the drug's binding to almost all cell lines which was reversed by incubation of cells with 2-hydroxy palmitic acid. The expression of fatty acid 2-hydroxylase was strongly correlated with the efficiency of the drug and inversely correlated with the effect of hypoxia. Number and brightness analysis and fluorescence anisotropy experiments showed that hypoxia decreased the clustering of lipid rafts and altered the structure of the plasma membrane. Although the binding of elisidepsin to the membrane is non-cooperative, its membrane permeabilizing effect is characterized by a Hill coefficient of ~3.3. The latter finding is in agreement with elisidepsin-induced clusters of lipid raft-anchored GFP visualized by confocal microscopy. We propose that the concentration of elisidepsin needs to reach a critical level in the membrane above which elisidepsin induces the disruption of the cell membrane. Testing for tumor hypoxia or the density of hydroxylated lipids could be an interesting strategy to increase the efficiency of elisidepsin.
埃利色丁（PM02734，Irvalec®）的作用机制被认为涉及通过攻击脂筏和羟化脂质来实现膜通透性。在这里，我们研究了缺氧在埃利色丁作用机制中的作用。在缺氧条件下培养会增加半最大抑制浓度，并使药物几乎与所有细胞系的结合减少，而用 2-羟基棕榈酸孵育细胞可逆转这种情况。脂肪酸 2-羟化酶的表达与药物的效率强烈相关，与缺氧的影响呈负相关。数量和亮度分析以及荧光各向异性实验表明，缺氧会减少脂筏的聚集并改变质膜的结构。尽管埃利色丁与膜的结合是非协同的，但它的膜通透性效应的希尔系数约为 3.3。这一发现与共聚焦显微镜观察到的埃利色丁诱导的质膜锚定 GFP 脂筏簇相一致。我们提出，埃利色丁在膜中的浓度需要达到一个临界水平，超过该水平，埃利色丁就会诱导细胞膜破裂。检测肿瘤缺氧或羟化脂质的密度可能是提高埃利色丁效率的一种有趣策略。
