Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.
Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.
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DOI：
10.1021/mp300281t
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发表时间：
2012-09-04
影响因子：
4.9
通讯作者：
Labhasetwar V
中科院分区：
文献类型：
--
作者：
Vijayaraghavalu S;Peetla C;Lu S;Labhasetwar V
在我们最近对耐药细胞脂的生物物理特性及其在药物转运中的作用的研究中，我们展示了耐药乳腺癌细胞与药物敏感细胞在脂组成和生物物理性质上的差异，提示癌细胞通过改变脂质合成来抑制细胞内药物转运来保护细胞毒作用，从而获得耐药表型。在癌细胞中，表观遗传变化(例如，DNA超甲基化)对于维持这种耐药表型是必不可少的。因此，脂质合成的改变可能与表观遗传耐药机制有关。我们假设，用表观遗传药物逆转耐药细胞中的DNA超甲基化可以改变脂质合成，改变细胞膜的生物物理性质，促进药物输送，以克服耐药性。在这里，我们发现，用表观遗传药物5-氮杂-2‘-脱氧胞苷(地他滨)处理耐药乳腺癌细胞(MCF-7/ADR)，显著改变细胞脂组成和生物物理性质，使耐药细胞获得类似于敏感细胞(MCF-7)脂类的生物物理特性。经地西他滨处理后，耐药细胞的鞘磷脂酶活性增加，导致鞘磷脂水平降低，从而影响脂段结构，增加膜流动性，并减少P-糖蛋白的表达。耐药细胞脂的生物物理特性的变化促进了阿霉素的转运，并恢复了阿霉素的内吞功能，从而提高了药物的疗效。总而言之，我们已经建立了一种新的机制，通过改变脂质成分和生物物理性质来调节表观遗传药物在逆转癌症耐药性方面的疗效。
In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane’s biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug, 5-aza-2′-deoxycytidine (decitabine), significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.
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影响因子：
2.1
作者：
Lo PK;Sukumar S
通讯作者：
Sukumar S
影响因子：
3.4
作者：
Rauch, C;Farge, E
通讯作者：
Farge, E
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：
4.9
作者：
Peetla C;Bhave R;Vijayaraghavalu S;Stine A;Kooijman E;Labhasetwar V
通讯作者：
Labhasetwar V
影响因子：
11.4
作者：
Chatterjee, S;Smith, ER;Mayor, S
通讯作者：
Mayor, S