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Investigation of expression regulatory mechanisms of drug transporters with its possible application for circumventing anticancer drug resistance

药物转运蛋白表达调控机制的研究及其在规避抗癌耐药性方面的可能应用

基本信息

批准号：
18590379
负责人：
IMAI Yasuo
金额：
$ 1.54万
依托单位：
Dokkyo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590379/
关键词：
Cancer Chemotherapy

项目摘要

ABCG2/BCRP, a member of the ATP-binding cassette transporter G family, functions as an efflux pump that excludes such anticancer agents as mitoxantrone, SN-38 (an active metabolite of irinotecan), and topotecan, across cell membrane. Accordingly ABCG2 causes multidrug resistance when overexpressed in cancer cells. We have thus far clarified that estrogen markedly down-regulates ABCG2 expression in estrogen receptor-positive breast cancer cells in the post-transcriptional manner, but use of estrogen in the practical clinic seemed to be limited due to its original physiological function.We then transfected ABCG2 cDNA to breast cancer MCF-7 cells and gastric cancer MKN1 and NCI-N87 cells, which express endogenous ABCG2, in order to exploring small molecules that affects ABCG2 expression levels, and termed them MCF-7/ABCG2, MKN1/ABCG2, and NCI-N87/ABCG2 cells.Exogenous ABCG2 protein expression in MCF-7/ABCG2, MKN1/ABCG2, NCI-N87/ABCG2 cells was markedly repressed by p44/p42 mitogen-activat … More ed protein kinase (MAPK), PD98059 and U0126, in the dose-dependent manner. These compounds almost completely overcame mitoxantrone- or SN-38- resistance of MCF-7/ABCG2 and NCI-N87/ABCG2 cells. FACS analyses revealed that the reversal effects were due to increased intracellular uptake of anticancer agents. Quantitative RT-PCR analyses demonstrated that ABCG2 mRNA levels were not affected by the treatment with PD98059 or U0126. In addition, a half life of the ABCG2 protein was significantly short in the presence of PD98059 as compared with that in the control experiment.PD98059-mediated degradation of ABCG2 protein was not affected by MG132, an ubiquitin/endosome inhibitor, but was completely blocked by bafilomycin A1, an endosomal inhibitor. These data suggest that inhibition of p44/p42 MAPK pathway may accelerate endosomal degradation of ABCG2 protein and makes it possible to overcome ABCG2-mediated multidrug resistance. These data may also suggest that p44/p42 MAPK inhibitors may serve for establishment of safe and effective chemotherapeutic regimen. Less

ABCG 2/BCRP是ATP结合盒转运蛋白G家族的成员，作为外排泵发挥作用，将米托蒽醌、SN-38（伊立替康的活性代谢产物）和托泊替康等抗癌药物排除在细胞膜之外。因此，当在癌细胞中过表达时，ABCG 2引起多药耐药性。我们已经阐明，雌激素通过转录后方式显著下调雌激素受体阳性乳腺癌细胞中ABCG 2的表达，但由于其原始生理功能，雌激素在实际临床中的使用似乎受到限制。我们随后将ABCG 2 cDNA转染到表达内源性ABCG 2的乳腺癌MCF-7细胞和胃癌MKN 1和NCI-N87细胞中，在MCF-7/ABCG 2、MKN 1/ABCG 2和NCI-N87/ABCG 2细胞中，外源性ABCG 2蛋白表达被p44/p42丝裂原激活剂显著抑制，而在MCF-7/ABCG 2、MKN 1/ABCG 2和NCI-N87/ABCG 2细胞中，外源性ABCG 2蛋白表达被p44/p42丝裂原激活剂显著抑制。 ...更多信息艾德蛋白激酶（MAPK）、PD 98059和U 0126呈剂量依赖性。这些化合物几乎完全克服了MCF-7/ABCG 2和NCI-N87/ABCG 2细胞的米托蒽醌或SN-38抗性。流式细胞仪分析表明，逆转作用是由于增加细胞内摄取的抗癌药物。定量RT-PCR分析表明，ABCG 2 mRNA水平不受PD 98059或U 0126处理的影响。PD 98059介导的ABCG 2蛋白降解不受MG 132（一种泛素/内体抑制剂）的影响，但被巴弗洛霉素A1（一种内体抑制剂）完全阻断。这些数据表明，抑制p44/p42 MAPK通路可能会加速ABCG 2蛋白的内体降解，从而使克服ABCG 2介导的多药耐药成为可能。这些数据也提示p44/p42 MAPK抑制剂可用于建立安全有效的化疗方案。少