Drug resistance in breast cancer cells: biophysical characterization of and doxorubicin interactions with membrane lipids.
Drug resistance in breast cancer cells: biophysical characterization of and doxorubicin interactions with membrane lipids.
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DOI：
10.1021/mp100308n
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发表时间：
2010-12-06
影响因子：
4.9
通讯作者：
Labhasetwar V
中科院分区：
文献类型：
--
作者：
Peetla C;Bhave R;Vijayaraghavalu S;Stine A;Kooijman E;Labhasetwar V
了解脂质在药物转运中的作用对于癌症化疗克服耐药性至关重要。在这项研究中，我们从阿霉素敏感（MCF-7）和耐药（MCF-7/ADR）乳腺癌细胞中分离脂质，以表征膜脂质的生物物理特性（特别是脂质包装和膜流动性），并了解细胞膜脂质与药物/纳米载体的相互作用对药物摄取和疗效的作用。耐药细胞膜脂质表现出显着不同的组合物，并形成更多的浓缩，更少的流体单层比敏感细胞的脂质。用作模型抗癌剂的多柔比星显示出与抗性细胞膜脂质的强疏水相互作用，但显著较少的相互作用，以及不同的相互作用模式（即，离子），与敏感的。敏感细胞系和耐药细胞系产生抗增殖作用所需的细胞内阿霉素浓度阈值相似，表明药物转运是决定耐药细胞中药物疗效的主要障碍。除了耐药细胞膜脂质的生物物理特性外，脂质-阿霉素相互作用似乎通过扩散降低细胞内药物转运，因为药物被捕获在脂质双层中。当使用阿霉素的脂质体制剂时，抗性细胞膜的刚性性质似乎也影响抑制药物摄取的内体功能。总之，耐药细胞膜脂质的生物物理性质显著影响药物转运，从而影响药物功效。更好地了解癌症耐药机制对于开发更有效的治疗干预至关重要。在这方面，与细胞膜脂质的生物物理相互作用研究可能有助于通过药物发现和/或药物递送方法克服耐药细胞中的脂质屏障来改善药物转运和功效。
Understanding the role of lipids in drug transport is critical in cancer chemotherapy to overcome drug resistance. In this study, we isolated lipids from doxorubicin-sensitive (MCF-7) and -resistant (MCF-7/ADR) breast cancer cells to characterize the biophysical properties of membrane lipids (particularly lipid packing and membrane fluidity) and to understand the role of the interaction of cell membrane lipids with drug/nanocarrier on drug uptake and efficacy. Resistant cell membrane lipids showed significantly different composition and formed more condensed, less fluid monolayers than did lipids from sensitive cells. Doxorubicin, used as a model anticancer agent, showed a strong hydrophobic interaction with resistant cell membrane lipids but significantly less interaction, as well as a different pattern of interaction (i.e., ionic), with sensitive ones. The threshold intracellular doxorubicin concentration required to produce an antiproliferative effect was similar for both sensitive and resistant cell lines, suggesting that drug transport is a major barrier in determining drug efficacy in resistant cells. In addition to the biophysical characteristics of resistant cell membrane lipids, lipid-doxorubicin interactions appear to decrease intracellular drug transport via diffusion as the drug is trapped in the lipid bilayer. The rigid nature of resistant cell membranes also seems to influence endosomal functions that inhibit drug uptake when a liposomal formulation of doxorubicin is used. In conclusion, biophysical properties of resistant cell membrane lipids significantly influence drug transport, and hence drug efficacy. A better understanding of the mechanisms of cancer drug resistance is vital to developing more effective therapeutic interventions. In this regard, biophysical interaction studies with cell membrane lipids might be helpful to improve drug transport and efficacy through drug discovery and/or drug delivery approaches by overcoming the lipid barrier in resistant cells.
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影响因子：
2.9
作者：
Demina, T;Grozdova, I;Melik-Nubarov, N
通讯作者：
Melik-Nubarov, N
影响因子：
4.8
作者：
Garcia-Saez, Ana J.;Chiantia, Salvatore;Schwille, Petra
通讯作者：
Schwille, Petra
影响因子：
2.9
作者：
DEWOLF, FA;STAFFHORST, RWHM;DEKRUIJFF, B
通讯作者：
DEKRUIJFF, B
影响因子：
5.3
作者：
Escribá PV;González-Ros JM;Goñi FM;Kinnunen PK;Vigh L;Sánchez-Magraner L;Fernández AM;Busquets X;Horváth I;Barceló-Coblijn G
通讯作者：
Barceló-Coblijn G
影响因子：
5.8
作者：
Elbayoumi, Tamer A.;Torchilin, Vladimir P.
通讯作者：
Torchilin, Vladimir P.