The interaction of sorafenib and regorafenib with membranes is modulated by their lipid composition
The interaction of sorafenib and regorafenib with membranes is modulated by their lipid composition
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DOI：
10.1016/j.bbamem.2016.08.014
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发表时间：
2016-11-01
影响因子：
3.4
通讯作者：
Mueller, Peter
中科院分区：
文献类型：
--
作者：
Haralampiev, Ivan;Scheidt, Holger A.;Mueller, Peter
索拉非尼和瑞格非尼是小分子激酶抑制剂，获批用于治疗局部复发性或转移性、进行性、分化型甲状腺癌、肾细胞癌和肝细胞癌（索拉非尼）以及结肠直肠癌（瑞格非尼）。到目前为止，负责其抗肿瘤活性的机制尚未完全了解。考虑到分子的亲脂性，可以假设药理学影响是通过与细胞膜的相互作用介导的，这对于许多具有生物活性的分子来说是真实的。然而，索拉非尼或瑞戈非尼与脂质膜的相互作用尚未详细研究。在这里，我们的特点是这两种药物与脂质膜的相互作用，通过应用各种生物物理方法，包括核磁共振，电子自旋共振和荧光光谱。我们发现索拉非尼和瑞格非尼通过插入双层的脂-水界面与脂膜结合。这种膜嵌入引起双层结构的扰动，导致膜对极性分子的渗透性增加。一种方法表明，影响的程度取决于膜脂质组成，强调磷脂酰胆碱和胆固醇的特定作用。我们的数据首次表征了索拉非尼和瑞格非尼对脂质膜结构和动力学的影响，这可能有助于更好地了解它们在治疗恶性肿瘤方面的有效性以及它们的副作用。(C)2016爱思唯尔B. V.保留所有权利。
Sorafenib and regorafenib are small-molecule kinase inhibitors approved for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma, renal cell carcinoma, and hepatocellular carcinoma (sorafenib) and of colorectal cancer (regorafenib). As of now, the mechanisms, which are responsible for their antitumor activities, are not completely understood. Given the lipophilic nature of the molecules, it can be hypothesized that the pharmacological impact is mediated by the interaction with cellular membranes as it is true for many pharmacologically active molecules. However, an interaction of sorafenib or regorafenib with lipid membranes has not yet been investigated in detail. Here, we characterized the interaction of both drugs with lipid membranes by applying a variety of biophysical approaches including nuclear magnetic resonance, electron spin resonance, and fluorescence spectroscopy. We found that sorafenib and regorafenib bind to lipid membranes by inserting into the lipid-water interface of the bilayer. This membrane embedding causes a disturbance of bilayer structure leading to an increased permeability of the membrane for polar molecules. One approach shows that the extent of the effects depends on the membrane lipid composition underlining a particular role of phosphatidylcholine and cholesterol. Our data for the first time characterize the impact of sorafenib and regorafenib on the lipid membrane structure and dynamics, which may contribute to a better understanding of their effectiveness in the treatment of malignancies as well as of their side effects. (C) 2016 Elsevier B.V. All rights reserved.