权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Analysis of the medical treatment resistance factor in salivary gland carcinoma

唾液腺癌耐药因素分析

基本信息

批准号：
20791557
负责人：
DOTO Ryosuke
金额：
$ 2.75万
依托单位：
Matsumoto Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2009
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20791557/
关键词：
ABC transporter MDR1 MRP1 GST 抗癌剤多剤耐性薬剤排泄機構 MDRl MRPl

项目摘要

Objectives : The poor clinical response of salivary gland adenocarcinoma (SGA) to combined chemotherapy for head-and-neck cancer (HNC) suggests that the sensitivities and/or mechanisms of resistance to anti-cancer drugs differ between SGA and oral squamous cell carcinoma (SCC). The present study aimed to clarify whether expression of the ATP-binding cassette (ABC) transporters MDR1 and MRP1 is associated with multidrug resistance (MDR) in HNC, and to determine differences in the associated processes between SGA and SCC.Materials and Methods: The expression of ABC transporters and glutathione S-transferase enzymes was studied immunohistochemically in the normal salivary gland and in cancer tissues from patients. Expression of MDR1 and MRP1 was analyzed using Western blotting in both SGA and SCC cell lines following vincristine administration. We also determined mdr1 and mrp1 mRNA expression levels using reverse transcriptase-polymerase chain reaction (RT-PCR).Results : Immunohistochemical analysis revealed MDR1 and MRP1 expression in ductal cells of salivary glands, but not in the oral mucosal epithelium. When compared with SCC, SGA displayed expressed more intense MRP1 and more MDR1. Analysis in vitro indicated more MDR1, MRP1 and glutathione S-transferase (GST)-pi class enzyme expression in drug-resistant SGA cells than in parental SGA or drug-resistant and drug-sensitive SCC cell lines. Immunoblotting and PCR confirmed that the expression of GST-pi was increased relative to that of MRP1 in drug-resistant SGA cells. The MDR1 inhibitor verapamil obviously enhanced cytotoxicity in resistant SGA and SCC cells at low vincristine concentrations. The GST inhibitor curcumin also enhanced cytotoxicity, particularly in resistant SGA cells after the MDR1 efflux barrier had been reversed by verapamil.Conclusion : These results indicate that MRP1/GST-pi enzymes are involved in the acquired-resistance phenotype of SGA.

目的：涎腺腺癌(SGA)对头颈癌联合化疗的临床疗效较差，提示SGA与口腔鳞状细胞癌(SCC)的抗癌药物敏感性和/或耐药机制不同。本研究旨在阐明三磷酸腺苷结合盒转运体mdr1和mrp1的表达与人涎腺癌多药耐药的关系，并探讨结合盒转运蛋白mdr1和mrp1在人涎腺癌多药耐药相关过程中的差异。材料和方法：应用免疫组织化学方法检测结合盒转运体和谷胱甘肽S转移酶在正常涎腺和癌组织中的表达。用Western blotting分析长春新碱对SGA和SCC细胞株MDR1和MRP1表达的影响。用逆转录聚合酶链式反应(RT-PCR)检测mdr1和mrp1mRNA的表达水平。结果：免疫组织化学显示mdr1和mrp1在涎腺导管细胞中有表达，而在口腔粘膜上皮中不表达。与SCC相比，SGA表达更强的MRP1和更多的mdr1。体外分析表明，耐药鳞状细胞癌耐药细胞mdr1、mrp1和谷胱甘肽S转移酶pi类酶的表达高于亲本细胞或耐药和敏感的鳞癌细胞。免疫印迹和聚合酶链式反应证实，耐药SGA细胞中GST-pi的表达相对MRP1的表达增加。MDR1抑制剂维拉帕米在低浓度长春新碱作用下可明显增强耐药SGA和SCC细胞的细胞毒作用。GST抑制剂姜黄素也增强了细胞毒作用，特别是在耐药的SGA细胞中，MDR1外排屏障被维拉帕米逆转后。结论：MRP1/GST-pi酶参与了SGA获得性耐药表型。