Multidrug resistance-associated protein 7 expression is involved in cross-resistance to docetaxel in salivary gland adenocarcinoma cell lines.
Multidrug resistance-associated protein 7 expression is involved in cross-resistance to docetaxel in salivary gland adenocarcinoma cell lines.
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DOI：
10.3892/ijo.30.2.393
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发表时间：
2007-02
影响因子：
5.2
通讯作者：
Hiroko Naramoto;T. Uematsu;T. Uchihashi;R. Doto;T. Matsuura;Y. Usui;S. Uematsu;Xianqi Li;Masahiro Takahashi;M. Yamaoka;K. Furusawa
中科院分区：
文献类型：
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作者：
Hiroko Naramoto;T. Uematsu;T. Uchihashi;R. Doto;T. Matsuura;Y. Usui;S. Uematsu;Xianqi Li;Masahiro Takahashi;M. Yamaoka;K. Furusawa
本研究的目的是阐明ATP结合盒转运蛋白是否是头颈部肿瘤的难治性因素。对于体外和体内化疗研究，我们使用以下头颈癌细胞系：小鼠口腔鳞状细胞癌（SCC）细胞系Sq-1979;人SCC细胞系SCCHA;小鼠唾液腺腺癌（SGA）细胞系NR-PG;和人SGA细胞系HSY。我们使用了一种长春花生物碱抗癌药物，长春新碱（VCR），作为化疗抗癌药物。为了确定多药耐药的原因，进行了Western印迹分析、逆转录-聚合酶链反应（RT-PCR）、裸鼠异种移植瘤的免疫组织化学、药物外排分析和药物外排抑制试验。VCR处理的细胞系Sq-1979/VCR、SCCHA/VCR、NR-PG/VCR和HSY/VCR强烈表达多药耐药（MDR）基因1 mRNA和多药耐药相关蛋白（MRP）1 mRNA。MRP 7 mRNA和蛋白在NR-PG/VCR和HSY/VCR细胞中表达，而在Sq-1979/VCR和SCCHA/VCR细胞中不表达。在NR-PG/VCR和HSY/VCR的每个细胞克隆中，VCR处理诱导了MRP 7 mRNA，表明在MRP 7表达的背景下对VCR的获得性耐药性。在体内化疗裸鼠模型中，VCR处理的异种移植SCCHA和HSY细胞表达MDR 1和MRP 1。此外，MRP 7表达在VCR注射的荷瘤小鼠的异种移植HSY细胞中，但在SCCHA细胞中没有。此外，在存在竞争性MRP 7抑制剂17-β-雌二醇-（17-β-D-葡糖苷酸）的情况下，HSY/VCR中多柔比星蓄积增加，多西他赛的药物交叉耐药性降低。这些结果表明，MDR 1的表达，MRP 1的表达，MRP 7的表达是难治性因素在头颈癌化疗，并建议诱导MRP 7的表达参与天然产物的耐药性，特别是多西他赛在SGA。
The aim of the present study was to clarify whether ATP binding cassette transporters are refractory factors in head and neck cancers. For in vitro and in vivo chemotherapeutic studies, we used the following head and neck cancer cell lines: a mouse oral squamous cell carcinoma (SCC) cell line, Sq-1979; a human SCC cell line, SCCHA; a mouse salivary gland adenocarcinoma (SGA) cell line, NR-PG; and a human SGA cell line, HSY. We used a vinca alkaloid anticancer drug, vincristine (VCR), as a chemotherapeutic anticancer drug. To determine the cause of multidrug resistance, Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry of xenografted tumors in nude mice, drug efflux analysis, and drug efflux inhibitory assays were performed. VCR-treated cell lines, Sq-1979/VCR, SCCHA/VCR, NR-PG/VCR, and HSY/VCR, intensively expressed multidrug resistance (MDR) gene 1 mRNA and multidrug resistance associated protein (MRP) 1 mRNA. MRP7 mRNA and protein were expressed in NR-PG/VCR and HSY/VCR cells, but not in Sq-1979/VCR and SCCHA/VCR cells. In each cell clone of NR-PG/VCR and HSY/VCR, MRP7 mRNA was induced by VCR treatment, suggesting an acquired resistance to VCR in the context of MRP7 expression. In the in vivo chemotherapeutic nude mice model, VCR-treated xenografted SCCHA and HSY cells expressed MDR1 and MRP1. Moreover, MRP7 expression was immunohistochemically found in xenografted HSY cells of VCR-injected tumor-bearing mice, but not in SCCHA cells. Furthermore, doxorubicin accumulation was increased and drug cross-resistance to docetaxel decreased in HSY/VCR in the presence of a competitive MRP7 inhibitor, 17-beta-estradiol-(17-beta-D-glucuronide). These results indicate that MDR1 expression, MRP1 expression, and MRP7 expression are refractory factors in head and neck cancer chemotherapy and suggest that induction of MRP7 expression is involved in drug resistance to natural products, especially to docetaxel in SGA.