Huang Ying, Blower Paul E, Liu Ruqing, Dai Zunyan, Pham Anh-Nhan, Moon Hojin, Fang Jialong, Sadée Wolfgang
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA.
Pharm Res. 2007 Sep;24(9):1702-12. doi: 10.1007/s11095-007-9300-x. Epub 2007 Apr 25.
A prerequisite for geldanamycin (GA, NSC122750) to targeting heat shock protein 90 and inhibiting tumor growth is sufficient intracellular drug accumulation. We hypothesized that membrane transporters on tumor cells determine at least in part the response to GA analogues.
To facilitate a systematic study of chemosensitivity across a group of GA analogues with similar chemical structures, we correlated mRNA expression profiles of most known transporters with growth inhibitory potencies of compounds in 60 tumor cell lines (NCI-60). We subsequently validated the gene-drug correlations using cytotoxicity and transport assays.
Geldanamycin analogues displayed a range of negative correlations coefficients with ABCB1 (MDR1, or P-glycoprotein) expression. Suppressing ABCB1 in multidrug resistant cells (NCI/ADR-RES and K562/DOX) and ABCB1-transfected cells (BC19) increased sensitivity to GA analogues, as expected for substrates. Moreover, ABCB1-mediated efflux of daunorubicin in K562/DOX cells could be blocked markedly by GA analogues in a dose-dependent fashion. The IC(50) values (half-maximum inhibition of daunorubicin efflux) were 5.5, 7.3 and 12 muM for macbecin II (NSC330500), 17-AAG (NSC330507) and GA, respectively.
These observations demonstrate that GA analogues are substrates as well as inhibitors of ABCB1, suggesting that drug interactions between GA analogues and other agents that are ABCB1 substrates may occur via ABCB1 in normal or tumor cells.
格尔德霉素（GA，NSC122750）靶向热休克蛋白90并抑制肿瘤生长的一个先决条件是细胞内有足够的药物蓄积。我们推测肿瘤细胞上的膜转运蛋白至少部分决定了对GA类似物的反应。
为便于对一组化学结构相似的GA类似物的化学敏感性进行系统研究，我们将60种肿瘤细胞系（NCI-60）中最知名转运蛋白的mRNA表达谱与化合物的生长抑制效力进行了关联。随后，我们使用细胞毒性和转运试验验证了基因-药物的相关性。
格尔德霉素类似物与ABCB1（多药耐药蛋白1，或P-糖蛋白）表达呈现一系列负相关系数。正如底物所预期的那样，在多药耐药细胞（NCI/ADR-RES和K562/DOX）以及ABCB1转染细胞（BC19）中抑制ABCB1可增加对GA类似物的敏感性。此外，GA类似物能以剂量依赖的方式显著阻断K562/DOX细胞中柔红霉素的ABCB1介导的外排。对于马贝西霉素II（NSC330500）、17-AAG（NSC330507）和GA，柔红霉素外排的IC50值（半最大抑制）分别为5.5、7.3和12μM。
这些观察结果表明GA类似物既是ABCB1的底物也是其抑制剂，这表明GA类似物与其他作为ABCB1底物的药物之间的药物相互作用可能在正常或肿瘤细胞中通过ABCB1发生。
