Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599-7360, United States.
Biomacromolecules. 2013 Feb 11;14(2):424-30. doi: 10.1021/bm301661w. Epub 2013 Jan 24.
Multidrug resistance (MDR) is a major barrier to the chemotherapy treatment of many cancers. However, some nonionic surfactants, for example, Brij, have been shown to restore the sensitivity of MDR cells to such drugs. The aim of this study was to explore the reversal effect of Brij on MDR tumor cells and elucidate its potential mechanism. Our data indicate that the structure of Brij surfactants plays an important role in overcoming MDR in cancer, that is, modified hydrophilic-lipophilic balance (MHLB, the ratio of the number (n) of hydrophilic repeating units of ethylene oxide (EO) to the number (m) of carbons in the hydrophobic tail (CH(2))). Cell viability of cells treated with paclitaxel (PTX) nanocrystals (NCs) formulated with Brij showed positive correlations with MHLB (R(2) = 0.8195); the higher the ratio of Brij to PTX in NCs, the higher cytotoxicity induced by the PTX NCs. Significant increases in intracellular accumulation of (3)H-PTX (P-gp substrate) were observed in an MDR cell line (H460/taxR cells) treated with Brij 78 (MHLB = 1.11) and Brij 97 (MHLB = 0.6). After treatments with Brij 78 and Brij 97, the levels of intracellular ATP were decreased and verapamil-induced ATPase activities of P-gp were inhibited in multidrug resistant cells. The responses of the cells to Brij 78 and Brij 97 in ATP depletion studies correlated with the cell viability induced by PTX/Brij NCs and intracellular accumulation of (3)H-PTX. Brij 78 and Brij 97 could not alter the levels of P-gp expression detected by Western blotting. These findings may provide some insight into the likelihood of further development of more potent P-gp inhibitors for the treatment of MDR in cancer.
多药耐药性（MDR）是许多癌症化疗治疗的主要障碍。然而，一些非离子表面活性剂，例如 Brij，已被证明可以恢复 MDR 细胞对这些药物的敏感性。本研究旨在探讨 Brij 对 MDR 肿瘤细胞的逆转作用，并阐明其潜在机制。我们的数据表明，Brij 表面活性剂的结构在克服癌症中的 MDR 方面起着重要作用，即修饰的亲水亲脂平衡（MHLB，亲水重复单元乙氧基（EO）的数量（n）与疏水尾部（CH（2））的碳原子数（m）之比）。用紫杉醇（PTX）纳米晶体（NCs）处理的细胞的细胞活力与 MHLB 呈正相关（R（2）= 0.8195）；NCs 中 Brij 与 PTX 的比例越高，PTX NCs 诱导的细胞毒性越高。在用 Brij 78（MHLB = 1.11）和 Brij 97（MHLB = 0.6）处理的 MDR 细胞系（H460/taxR 细胞）中观察到（3）H-PTX（P-糖蛋白底物）的细胞内积累显著增加。用 Brij 78 和 Brij 97 处理后，多药耐药细胞内的细胞内 ATP 水平降低，维拉帕米诱导的 P-糖蛋白 ATP 酶活性受到抑制。细胞对 Brij 78 和 Brij 97 的反应与 PTX/Brij NCs 诱导的细胞活力和（3）H-PTX 的细胞内积累相关。Brij 78 和 Brij 97 不能改变 Western blot 检测到的 P-糖蛋白表达水平。这些发现可能为进一步开发更有效的 P-糖蛋白抑制剂治疗癌症中的 MDR 提供一些思路。
