Nieth C, Lage H
Charité Campus Mitte, Institute of Pathology, Schumannstr. 20/21, D-10117 Berlin, Germany.
J Chemother. 2005 Apr;17(2):215-23. doi: 10.1179/joc.2005.17.2.215.
Resistance to mitoxantrone is often associated with enhanced drug efflux mediated by members of the superfamily of adenosinetriphosphate-binding cassette (ABC) transporters, i.e. MDR1/P-gp (ABCB1), MRP1 (ABCC1), or BCRP (ABCG2). So far it is unclear whether the same ABC-transporter is always activated from the beginning of mitoxantrone treatment to the end of drug exposure. Here, we demonstrate that the expression of all three extrusion pumps is induced by increasing levels of mitoxantrone resistance, but in the end, merely the overexpression of a dominant single drug transporter, i.e. Mdr1/P-gp, is realized. This upregulation of Mdr1/P-gp was reflected by amplification of the Mdr1/P-gp encoding gene. Short mitoxantrone exposure demonstrated that upregulation of two different transporters, Mdr1/P-gp and Bcrp, was induced. The data indicate that mitoxantrone treatment influences the expression of several ABC-transporters, but in the end, merely a single extrusion pump will be dominant.
对米托蒽醌的耐药性通常与三磷酸腺苷结合盒（ABC）转运蛋白超家族成员介导的药物外排增强有关，即多药耐药蛋白1/ P-糖蛋白（MDR1/P-gp，ABCB1）、多药耐药相关蛋白1（MRP1，ABCC1）或乳腺癌耐药蛋白（BCRP，ABCG2）。到目前为止，尚不清楚从米托蒽醌治疗开始到药物暴露结束是否总是激活相同的ABC转运蛋白。在此，我们证明所有三种外排泵的表达均随着米托蒽醌耐药水平的升高而诱导，但最终仅实现了一种主要单一药物转运蛋白即Mdr1/P-gp的过表达。Mdr1/P-gp的这种上调通过Mdr1/P-gp编码基因的扩增得以体现。短期米托蒽醌暴露表明，Mdr1/P-gp和Bcrp这两种不同转运蛋白的上调被诱导。数据表明，米托蒽醌治疗会影响几种ABC转运蛋白的表达，但最终只有一种外排泵占主导地位。
