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首页> 外文期刊>Biochemistry >P-Glycoprotein-Mediated Colchicine Resistance in Different Cell Lines Correlates with the Effects of Colchicine on P-Glycoprotein Conformation
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P-Glycoprotein-Mediated Colchicine Resistance in Different Cell Lines Correlates with the Effects of Colchicine on P-Glycoprotein Conformation

机译：P-糖蛋白介导的不同细胞系秋水仙碱抗性与秋水仙碱对P-糖蛋白构象的影响相关

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摘要

The multidrug transporter P-glycoprotein (Pgp) is an ATPase efflux pump for multiple cytotoxic agents, including vinbiastine and colehicine. We have found that resistance to vinbiastine but not to coichicine in cell lines derived from different types of tissues and expressing the wild-type human Pgp correlates with the Pgp density. Vinblastine induces a conformational change in Pgp, evidenced by increased reactivity with a conformation-sensitive monoclonal antibody UIC2, in all the tested cell lines. In contrast, colchicine increases the UIC2 reactivity in only some of the cell lines. In those lines where colchicine alone did not affect UJC2 reactivity, this drug was, however, able to reverse the vinbiastine-induced increase in UIC2 reactivity. The magnitude of the increase in UJC2 reactivity in the presence of saturating concentrations of colchicine correlates with the relative ability of Pgp to confer colchicine resistance in different cell lines, suggesting the existence of some cell-specific factors that have a coordinate effect on the ability of colchicine to induce conformational transitions and to be transported by Pgp. Colchicine, like vinblastine, reverses the decrease in UIC2 reactivity produced by nonhydrolyzable nucleotides, but unlike vinbiastine, it does not reverse the effect of ATP at a high concentration. Colchicine, however, decreases the Hill number for the effect of ATP on the UIC2 reactivity from 2 to 1. Colchicine increases the UIC2 reactivity and reverses the effect of ATP in ATPase-deficient Pgp mutants, but not in the wild-type Pgp expressed in the same cellular background, suggesting that ATP hydrolysis counteracts the effects of colchicine on the Pgp conformation.
机译：多药转运蛋白P糖蛋白（Pgp）是ATPase外排泵，用于多种细胞毒剂，包括长春新碱和秋水仙碱。我们已经发现，在源自不同类型组织并表达野生型人Pgp的细胞系中对长春新碱的抗性而非对联苯胺的抗性与Pgp密度相关。在所有测试的细胞系中，长春碱会诱导Pgp发生构象变化，这一点可通过与构象敏感的单克隆抗体UIC2的反应性增强来证明。相反，秋水仙碱仅在一些细胞系中增加UIC2反应性。在那些单独使用秋水仙碱不会影响UJC2反应性的品系中，该药物能够逆转长春新碱引起的UIC2反应性增加。在饱和浓度的秋水仙碱存在下，UJC2反应性增加的幅度与Pgp在不同细胞系中赋予秋水仙碱抗性的相对能力有关，表明存在一些细胞特异性因子，这些因子对细胞凋亡的能力具有协同作用。秋水仙碱诱导构象转变并被Pgp转运。像长春碱一样，秋水仙碱可以逆转不可水解核苷酸产生的UIC2反应性的降低，但与长春新碱不同，它不能逆转高浓度的ATP的作用。然而，秋水仙碱可将ATP对UIC2反应性的影响的Hill数从2降低到1。秋水仙碱可提高UIC2反应性，并逆转ATP酶缺乏的Pgp突变体中ATP的作用，但不会影响野生型Pgp中的表达。相同的细胞背景，表明ATP水解抵消了秋水仙碱对Pgp构象的影响。

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