Enhanced delivery of cisplatin to intraperitoneal ovarian carcinomas mediated by the effects of bortezomib on the human copper transporter 1.
Enhanced delivery of cisplatin to intraperitoneal ovarian carcinomas mediated by the effects of bortezomib on the human copper transporter 1.
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DOI：
10.1158/1078-0432.ccr-08-2081
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发表时间：
2009-01-15
期刊：
影响因子：
--
通讯作者：
Howell SB
中科院分区：
文献类型：
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作者：
Jandial DD;Farshchi-Heydari S;Larson CA;Elliott GI;Wrasidlo WJ;Howell SB
铜转运蛋白1（CTR 1）是铂类药物的主要内流转运蛋白。然而，顺铂在人卵巢癌细胞中的积累受到顺铂触发CTR 1的下调和蛋白酶体降解从而限制其自身摄取的事实的限制。我们试图确定使用硼替佐米抑制蛋白酶体是否会阻止人CTR 1（hCTR 1）降解并增加卵巢癌细胞中铂的积累。通过Western印迹、流式细胞术和共聚焦数字成像分析来测量硼替佐米对人hCTR 1表达和顺铂蓄积的影响。铂的积累，测定电感耦合等离子体质谱法和硼替佐米浓度的液相色谱/质谱法。硼替佐米以浓度依赖性方式阻断顺铂诱导的hCTR 1下调，并使顺铂摄取增加1.6至2.4倍。中位效应分析显示，在50%细胞杀伤率下，组合指数为0.37，表明具有高水平的协同作用。硼替佐米的作用在缺乏CTR 1的两个等位基因的细胞中减弱，表明硼替佐米主要通过其阻断hCTR 1降解的作用起作用。在小鼠模型中，硼替佐米腹膜内给药产生的腹膜/血浆曲线下面积比为252。在腹膜内顺铂之前腹膜内给予硼替佐米使腹膜肿瘤中的铂蓄积增加33%（P = 0.006）。蛋白酶体抑制阻止顺铂诱导的卵巢癌细胞中hCTR 1的下调，并以协同方式增强药物摄取和细胞杀伤。硼替佐米在腹膜内给药时显示出很大的药理学优势。硼替佐米和顺铂联合腹膜内给药有很强的理由。
The copper transporter 1 (CTR1) is a major influx transporter for platinum drugs. However, the accumulation of cisplatin in human ovarian carcinoma cells is limited by the fact that cisplatin triggers the down-regulation and proteasomal degradation of CTR1, thereby limiting its own uptake. We sought to determine whether proteasome inhibition using bortezomib would prevent human CTR1 (hCTR1) degradation and increase platinum accumulation in ovarian cancer cells. The effects of bortezomib on human hCTR1 expression and cisplatin accumulation were measured by Western blot, flow cytometric, and confocal digital imaging analyses. Platinum accumulation was measured by inductively coupled plasma mass spectrometry and bortezomib concentrations by liquid chromatography/mass spectrometry. Bortezomib blocked the cisplatin-induced down-regulation of hCTR1 in a concentration-dependent manner and increased cisplatin uptake 1.6- to 2.4-fold. Median effect analysis showed a combination index of 0 .37 at 50% cell kill, indicating a high level of synergy. The effect of bortezomib was muted in cells lacking both alleles of CTR1, showing that bortezomib was working primarily through its effect on blocking hCTR1 degradation. I.p. administration of bortezomib produced a peritoneal/plasma area under the curve ratio of 252 in a murine model. I.p. administration of bortezomib before i.p. cisplatin increased platinum accumulation in peritoneal tumors by 33% (P = 0.006). Proteasomal inhibition prevented cisplatin-induced down-regulation of hCTR1 in ovarian cancer cells and enhanced drug uptake and cell killing in a synergistic manner. Bortezomib shows a large pharmacologic advantage when administered i.p. There is a strong rationale for the combined i.p. administration of bortezomib and cisplatin.