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Sensitizing gastric adenocarcinoma to chemotherapy by pharmacological manipulation of drug transporters

机译：用药物运输司机的药理操纵致胃腺癌与化疗

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Owing to intrinsic and acquired chemoresistance, the response of gastric adenocarcinoma (GAC) to chemotherapy is very poor. Here we have investigated the role of transportome in reducing the intracellular content of anticancer drugs and conferring multidrug resistance (MDR) phenotype. Tumors specimens and paired adjacent tissue were analyzed to determine the MDR signature by TaqMan Low-Density Arrays and single-gene qPCR. Strategies of sensitization were evaluated in vitro using the GAC-derived cell line AGS and in vivo using a subcutaneous xenograft model in immunodeficient nude mice. Several transporters involved in drug uptake and export, which are present in healthy stomach, were highly expressed in GAC. In contrast, the cancer-type OATP1B3 was almost exclusively expressed in tumor tissue. The transportome profile varied depending on tumor anatomical location, differentiation, and stage. Immunofluorescence analysis revealed high MRP1 and MRP4 expression at the plasma membrane of tumor cells as well as AGS cells in culture, in which MRP inhibition resulted in selective sensitization to cytotoxic MRP substrates, such as sorafenib, docetaxel, etoposide, and doxorubicin. In mice with subcutaneous tumors formed by AGS cells, sorafenib alone failed to prevent tumor growth. In contrast, this drug induced a marked inhibitory effect when it was co-administered with diclofenac. In conclusion, MRP1 and MRP4 play an important role in the lack of response of GAC to drugs that are transported by these export pumps. Moreover, agents, such as sorafenib, considered at present useless to treat GAC, may become active antitumor drugs when co-administered with non-toxic MRP inhibitors, such as diclofenac.
机译：由于内在和获得的化学抑制性，胃腺癌（GAC）对化疗的反应非常差。在这里，我们研究了逆转录在降低抗癌药物细胞内含量和赋予多药耐药性（MDR）表型的作用。分析肿瘤标本和配对的相邻组织以通过Taqman低密度阵列和单基因QPCR确定MDR签名。在免疫缺陷裸鼠中使用GAC衍生的细胞系AG和体内，在体外评估致敏感策略。参与药物摄取和出口的几种运输扣，其存在于健康的胃中，在GAC中高度表达。相反，癌症型oatp1b3几乎完全在肿瘤组织中表达。转运轮廓根据肿瘤解剖学位置，分化和阶段而变化。免疫荧光分析显示肿瘤细胞质膜的高MRP1和MRP4表达以及培养中的AGS细胞，其中MRP抑制导致细胞毒性MRP基材的选择性敏感，例如索拉非尼，多西紫杉醇，依托泊苷和多柔比星。在由AGS细胞形成的皮下肿瘤形成的小鼠中，单独的Sorafenib未能预防肿瘤生长。相比之下，当它与双氯芬酸共同施用时，这种药物诱导显着的抑制作用。总之，MRP1和MRP4在GAC对由这些出口泵运输的药物缺乏反应中起重要作用。此外，当与非有毒MRP抑制剂（例如双氯芬酸）共同施用时，索拉非尼被认为无用的索拉非尼被认为无用的药物可能成为活性抗肿瘤药物。

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