Modulation of OATP1B-type transporter function alters cellular uptake and disposition of platinum chemotherapeutics.
Modulation of OATP1B-type transporter function alters cellular uptake and disposition of platinum chemotherapeutics.
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DOI：
10.1158/1535-7163.mct-12-0926
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发表时间：
2013-08
影响因子：
5.7
通讯作者：
Sparreboom A
中科院分区：
文献类型：
--
作者：
Lancaster CS;Sprowl JA;Walker AL;Hu S;Gibson AA;Sparreboom A
以前认为人有机阴离子转运多肽OATP 1B1和OATP 1B3的表达仅限于肝细胞。在这里，我们证明了基因编码OATP1B3，而不是OATP1B1，是丰富的表达在多种人类实体瘤，包括肝细胞癌，肺癌和卵巢癌。令人惊讶的是，一组60种人类肿瘤细胞系中的OATP1B3表达与对多种细胞毒性药物的敏感性相关，包括铂类抗癌药物顺铂、卡铂和奥沙利铂。此外，OATP 1B3在哺乳动物细胞中的过表达增加了铂类药物的细胞蓄积并降低了细胞存活率。在小鼠的直系同源转运蛋白Oatp1b2有针对性的破坏，顺铂的肝脏与血浆的比例显着降低与野生型小鼠相比，没有其他转运蛋白基因的表达谱的同时变化。我们的研究结果表明，肿瘤和宿主OATP1B型载体在铂类抗癌药物的毒性和处置中发挥了意想不到的作用，并可能为理解这些药物在患者中观察到的广泛的个体间药效学变异性提供基础。
Expression of the human organic anion transporting polypeptides OATP1B1 and OATP1B3 have been previously believed to be restricted to hepatocytes. Here we demonstrate that the gene encoding OATP1B3, but not OATP1B1, is abundantly expressed in multiple human solid tumors that include hepatocellular, lung, and ovarian carcinomas. Surprisingly, OATP1B3 expression in a panel of 60 human tumor cell lines was linked with sensitivity to multiple cytotoxic agents, including the platinum anticancer drugs cisplatin, carboplatin, and oxaliplatin. In addition, overexpression of OATP1B3 in mammalian cells increased cellular accumulation of platinum agents and decreased cell survival. In mice with a targeted disruption of the ortholog transporter Oatp1b2, the liver-to-plasma ratio of cisplatin was significantly reduced compared with wildtype mice, without concurrent changes in expression profiles of other transporter genes. Our findings indicate an unexpected role for tumoral and host OATP1B-type carriers in the toxicity and disposition of platinum anticancer drugs, and may provide a foundation for understanding the extensive interindividual pharmacodynamic variability seen with these drugs in patients.