Rapid doxorubicin efflux from the nucleus of drug-resistant cancer cells following extracellular drug clearance
Rapid doxorubicin efflux from the nucleus of drug-resistant cancer cells following extracellular drug clearance
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DOI：
10.1007/s11095-007-9369-2
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发表时间：
2007-11-01
影响因子：
3.7
通讯作者：
Rosania, Gus R.
中科院分区：
文献类型：
--
作者：
Chen, Vivien Y.;Posada, Maria M.;Rosania, Gus R.
在细胞外药物清除后，我们分析了三种人白血病细胞（K562，Molt 4和CCRF-CEM）在短的药物脉冲后从细胞核流出阿霉素的速率，并将其与它们对这种药物的不同敏感性联系起来。在K562细胞中，核药物积聚最大，但核药物排出也最大。多柔比星耐药的K562/DOX亚系中P-糖蛋白的过度表达并不能促进多柔比星从细胞核流出。在K562细胞中，阿霉素通过pH依赖性机制在多泡体（MVB）中蓄积。抑制MVB中的药物螯合并不影响核外排。阿霉素从活的和毛地黄皂苷透化的K562细胞的细胞核流出的速率是相似的。然而，提取细胞质膜与Triton X-100显着抑制细胞外药物clearation.Our结果是一致的药物从细胞核流出主要是由ATP介导的非依赖性，被动扩散机制。膜提取的效果表明，非特异性药物吸收到细胞质膜中起着促进K562细胞核外排的作用，可能是通过降低游离阿霉素的浓度从核周扩散边界层。
Following extracellular drug clearance, we analyzed the rate of doxorubicin efflux from the nucleus of three human leukemic cells (K562, Molt4 and CCRF-CEM) and related it to their differential sensitivity to this drug, after a short drug pulse.For many pulse-chase regimes, K562 cell viability was least affected by doxorubicin. In K562 cells, nuclear drug accumulation was greatest, but nuclear drug egress was also greatest. P-glycoprotein over-expression in a doxorubicin-resistant, K562/DOX sub-line did not facilitate doxorubicin efflux from the nucleus. In K562 cells, doxorubicin accumulated in multivesicular bodies (MVBs) through a pH-dependent mechanism. Inhibiting drug sequestration in MVBs did not affect nuclear efflux. The rates of doxorubicin efflux from the nuclei of live and digitonin-permeabilized K562 cells were similar. However, extracting cytoplasmic membranes with Triton X-100 significantly inhibited nuclear drug efflux following extracellular drug clearance.Our results are consistent with drug efflux from the nucleus being primarily mediated by an ATP-independent, passive diffusion mechanism. The effect of membrane extraction suggests that nonspecific drug absorption to cytoplasmic membranes plays a role in facilitating nuclear efflux in K562 cells, perhaps by lowering the concentration of free doxorubicin from a perinuclear diffusion boundary layer.