Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein.
Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein.
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DOI：
10.1016/s0021-9258(18)61633-3
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发表时间：
1987-02
期刊：
影响因子：
--
通讯作者：
M. Cornwell;I. Pastan;M. Gottesman
中科院分区：
文献类型：
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作者：
M. Cornwell;I. Pastan;M. Gottesman
钙通道阻滞剂维拉帕米和地尔硫卓已被证明可以逆转多药耐药，但这些药物的作用机制仍不清楚。我们测量了[3 H]维拉帕米、[3 H]去甲氧基维拉帕米、[3 H]地尔硫卓和[3 H]尼群地平与由药物敏感细胞（KB-3-1）、多药耐药细胞（KB-C4和KB-V1）和回复突变细胞（KB-V1-R2）制成的膜囊泡的结合。与亲本KB-3-1或回复突变体KB-V1-R2细胞系的囊泡相比，KB-V1细胞的膜囊泡结合的[3 H]维拉帕米和[3 H]地尔硫卓多10-20倍，[3 H]去甲氧基维拉帕米多约30倍。这些药物通过增加耐药细胞中药物的积累来逆转多药耐药表型。观察到[3 H]尼群地平的结合没有差异，尼群地平不逆转耐药性。长春碱、去甲氧基维拉帕米和地尔硫卓与KB-V1囊泡的结合具有特异性和饱和性，去甲氧基维拉帕米和奎尼丁的抑制作用大于长春碱，地尔硫卓的抑制作用大于柔红霉素。此外，维拉帕米和地尔硫卓抑制长春碱光亲和标记的P170，蛋白质先前被证明是多药耐药的标志物。
The calcium channel blockers verapamil and diltiazem have been shown to reverse multidrug resistance, but the mechanism of action of these agents is still unknown. We measured [3H]verapamil, [3H]desmethoxyverapamil, [3H]diltiazem, and [3H]nitrendipine binding to membrane vesicles made from drug-sensitive (KB-3-1), multidrug-resistant (KB-C4 and KB-V1), and revertant (KB-V1-R2) cells. Membrane vesicles from KB-V1 cells bound 10-20-fold more [3H]verapamil and [3H]diltiazem and about 30-fold more [3H]desmethoxyverapamil than did vesicles from the parental KB-3-1 or revertant KB-V1-R2 cell lines. These drugs reverse the multidrug resistance phenotype by increasing accumulation of drugs in the resistant cells. No difference in binding of [3H]nitrendipine, which did not reverse drug resistance, was observed. The binding of vinblastine, desmethoxyverapamil, and diltiazem to KB-V1 vesicles was specific and saturable and was inhibited by desmethoxyverapamil and quinidine greater than vinblastine and diltiazem much greater than daunomycin. In addition, verapamil and diltiazem inhibited the vinblastine photoaffinity labeling of P170, the protein previously shown to be a marker of multidrug resistance.