Morjani H, Belhoussine R, Lahlil R, Manfait M
Laboratory of Biomolecular Spectroscopy, University of Reims Champagne-Ardenne, IFR53, UPRES EA2063, Faculty of Pharmacy, France.
Eur J Haematol. 1998 Oct;61(4):240-9. doi: 10.1111/j.1600-0609.1998.tb01709.x.
A number of small and lipophilic cations are able to reverse in vitro the resistance to anthracyclines and other natural products through their interaction with P-glycoprotein or P-gp. However, some modulators do not interact with P-gp. We have demonstrated in a previous a work, using confocal laser microspectrofluorometry, that quinine does not increase nuclear anthracycline uptake in multidrug-resistant Chinese hamster ovary LR73 cells. In this case the LR73 cells were transfected with the mdr1 gene. Moreover, quinine induced in these cells an increase of mdr1 gene expression. In the present study, we investigated verapamil and quinine for their ability to increase nuclear pirarubicin uptake in multidrug-resistant K562R and CEMR human leukemic cell lines. These two cell lines resist, respectively, to doxorubicin and vinblastine and both overexpress the P-gp. Verapamil was able to restore nuclear pirarubicin in both cell lines. On the other hand, quinine was unable to significantly increase nuclear pirarubicin uptake. Both modulators were able to restore pirarubicin sensitivity in both resistant cell lines. After treatment with quinine, mdr1 gene and P-gp expression was not significantly altered as observed previously in the LR73 cells. This suggest that the effect of quinine on mdr1 gene expression is dependent on the cell line studied. These data suggest that quinine could modify the molecular environment of anthracyclines and/or its binding to a possible cytoplasmic target, and that the mechanisms by which anthracyclines induce cell death, and ways by which chemotherapy fails in multidrug-resistant leukemic cells remain complex and are related to more than one target.
一些小分子亲脂性阳离子能够通过与P-糖蛋白（P-gp）相互作用，在体外逆转对蒽环类药物和其他天然产物的耐药性。然而，一些调节剂并不与P-gp相互作用。我们在之前的一项工作中，使用共聚焦激光显微荧光测定法证明，奎宁不会增加多药耐药的中国仓鼠卵巢LR73细胞中蒽环类药物的核摄取。在这种情况下，LR73细胞用mdr1基因进行了转染。此外，奎宁在这些细胞中诱导mdr1基因表达增加。在本研究中，我们研究了维拉帕米和奎宁增加多药耐药的K562R和CEMR人白血病细胞系中吡柔比星核摄取的能力。这两种细胞系分别对阿霉素和长春碱耐药，且均过度表达P-gp。维拉帕米能够在两种细胞系中恢复吡柔比星的核摄取。另一方面，奎宁无法显著增加吡柔比星的核摄取。两种调节剂都能够恢复两种耐药细胞系中吡柔比星的敏感性。用奎宁处理后，mdr1基因和P-gp表达没有像之前在LR73细胞中观察到的那样发生显著改变。这表明奎宁对mdr1基因表达的影响取决于所研究的细胞系。这些数据表明，奎宁可能会改变蒽环类药物的分子环境和/或其与可能的细胞质靶点的结合，并且蒽环类药物诱导细胞死亡的机制以及化疗在多药耐药白血病细胞中失败的方式仍然很复杂，并且与多个靶点相关。
