肺耐药蛋白与肿瘤细胞多药耐药研究进展

肺耐药蛋白(LRP)是一种与肿瘤细胞多药耐药(MDR)有关的蛋白质，是人类的穹窿体主蛋白(MVP)。它通过减少化疗药物在细胞核和细胞质之间的比例以及改变化疗药物在细胞质内的再分布而介导肿瘤细胞产生MDR。检测肿瘤组织中LRP的表达情况，对于部分肿瘤临床治疗的选择以及预测临床疗效具有一定参考价值。     

多药耐药相关蛋白3的研究进展

多药耐药相关蛋白(MRP)家族属于人类三磷酸腺苷结合盒转运蛋白超家族,MRP3是其中之一,可以转运与谷胱甘肽、硫酸盐、葡萄糖醛酸酯结合的有机化合物.MRP3在正常肝脏、胰腺、肠道和一些肿瘤中表达,在胆汁淤积情况下其表达可被诱导.MRP3参与了胆盐代谢、肝肠循环、内外源性代谢废物的排泄,并且在肿瘤的多药耐药机制中发挥重要的作用.     

多药耐药相关蛋白及其逆转剂的研究进展

多药耐药相关蛋白(MRP)是一种ATP依赖型跨膜蛋白，是谷胱甘肽(GSH)-S-共轭物运转泵，在GSH参与下，转运共轭的有机阴离子，起到药物外排泵的作用，是继P-170糖蛋白后发现的又一肿瘤多药耐药(MDR)机制。在一些肿瘤组织中，MRP的表达显著增高。它可能是肿瘤细胞发生耐药的重要机制。化学逆转剂可能具有逆转由MRP介导的MDR，从而增加肿瘤细胞对化疗药物的敏感性，克服耐药，提高化疗效果。     

多药耐药相关蛋白及其逆转剂的研究进展

多药耐药相关蛋白(MRP)是一种ATP依赖型跨膜蛋白,是谷胱甘肽(GSH)-S-共轭物运转泵,在GSH参与下,转运共轭的有机阴离子,起到药物外排泵的作用,是继P-170糖蛋白后发现的又一肿瘤多药耐药(MDR)机制.在一些肿瘤组织中,MRP的表达显著增高.它可能是肿瘤细胞发生耐药的重要机制.化学逆转剂可能具有逆转由MRP介导的MDR,从而增加肿瘤细胞对化疗药物的敏感性,克服耐药,提高化疗效果.     

多药耐药基因及相关耐药蛋白在肿瘤中的研究进展

化疗是肿瘤治疗的重要方法之一,但多药耐药(MDR)一直是影响其疗效的主要因素.肿瘤细胞中MDR1基因的扩增及其相关耐药蛋白的过度表达,细胞周期和细胞凋亡通路的信号转导相关机制的改变等,是导致化疗失败的重要原因.     

多药耐药相关蛋白1与肿瘤

多药耐药相关蛋白（MRP）家族与P-糖蛋白同属人ABC转运蛋白超家族,介导肿瘤细胞的多药耐药,目前已发现7个成员.MRP1是190kD的跨膜糖蛋白,MRP1与P-糖蛋白介导的多药耐药有诸多差异.现综述MRP1的结构、主要生理功能、转运底物、转运功能的调控和逆转及其在肿瘤研究中的意义等方面的研究进展.     

多药耐药相关蛋白1与肿瘤

多药耐药相关蛋白(MRP)家族与P-糖蛋白同属人ABC转运蛋白超家族,介导肿瘤细胞的多药耐药,目前已发现7个成员.MRP1是190kD的跨膜糖蛋白,MRP1与P-糖蛋白介导的多药耐药有诸多差异.现综述MRP1的结构、主要生理功能、转运底物、转运功能的调控和逆转及其在肿瘤研究中的意义等方面的研究进展.     

多药耐药相关蛋白—肿瘤耐药研究新进展

多药耐药相关蛋白———肿瘤耐药研究新进展谢剑明（综述）李金瀚熊世钢（审校）肿瘤化学治疗最大障碍之一是肿瘤细胞对药物的耐受性。１９７０年Ｂｉｅｄｌｅｒ等〔１〕用中国仓鼠肺细胞系和骨髓纤维母细胞系，与放线菌素Ｄ（ＡＣＴＤ）接触培养诱导耐药，发现它们不仅对...     

多药耐药相关蛋白1在三种乳腺癌细胞系中表达差异的研究

 目的　比较多药耐药相关蛋白1（MRP1）在人类乳腺癌敏感细胞（MCF-7／S）和耐药细胞（MCF-7／TAM、MCF-7／ADR）中的表达差异。初步探索乳腺癌细胞对三苯氧胺（TAM）和多柔比星（ADR）的耐药性的发生机制。方法　分别采用实时荧光定量PCR、Western blot技术检测MRP1基因和MRP1蛋白在3种乳腺癌细胞中的表达差异。结果　MRP1 mRNA在MCF-7／TAM和MCF-7／ADR细胞中表达量分别是MCF-7／S细胞的（2.63±0.18）倍和（8.38±0.76）倍,差异均有统计学意义（P＝0.004,P＝0.003）。MRP1蛋白在MCF-7／TAM细胞和MCF-7／ADR细胞中表达均高于MCF-7／S细胞,与MRP1 mRNA的趋势相一致。结论　MRP1的高表达可能是乳腺癌细胞对TAM和ADR产生耐药的共同发生机制。     

多药耐药相关蛋白7及其抑制剂

多药耐药(MDR)的机制与转运蛋白有关,现在研究最多的为P-糖蛋白(P-gp)、多药耐药相关蛋白(MRP)1、乳腺癌耐药相关蛋白(BCRP)等的抑制剂.MRP7可介导对紫杉醇、长春新碱和长春碱等的耐药.MRP7抑制剂近年研究主要包括千斤藤素、酪氨酸酶抑制剂、环孢素A等,MDR是多种机制共同作用的结果,对其他转运体的研究会提供更全面、更广泛的MDR逆转途径.     

肺癌多药耐药性机制研究进展

多药耐药是肺癌药物治疗失败的重要原因。克服多药耐药障碍是肺癌基础和临床研究的重点。Pgp，多药耐药相关蛋白和肺耐药相关蛋白等药物外排泵机制，是目前研究最广泛深入的机制。     

Effect of lung resistance-related protein on the resistance to cisplatin in human ovarian cancer cell lines

The mechanisms of drug-resistance in human ovarian cancer cells have not been entirely clarified. The purpose of this study was to investigate whether LRP is involved in the resistance of ovarian cancer cell lines to cisplatin and its molecular mechanism. Human ovarian cisplatin-resistant cancer cell lines (A2780/DDP and COC1/DDP) and their parental cisplatin-sensitive cell lines (A2780 and COC1), alone or transfected with antisense LRP-specific oligonucleotides (ODN) or sense ODN, were treated with cisplatin to induce differentiation. Expression of LRP was examined by RT-PCR and Western blot analysis. The sensitivities of cells to cisplatin were assessed using sulforhodamine B (SRB) assay and flow cytometry, and the accumulation and efflux of cisplatin in the cells and isolated nuclei were examined by high performance liquid chromatographic (HPLC) assay. The expressions of LRP in A2780/DDP and COC1/DDP cells were higher than those in A2780 and COC1 cells and conferred resistance to cisplatin. Transfection of LRP AsODN into A2780/DDP and COC1/DDP cells down-regulated LRP expression and reversed the resistance phenotype. Levels of cisplatin accumulating in cells were increased by LRP-specific AsODN and anti-LRP monoclonal antibody. Isolated nuclei from A2780 and COC1 cells or A2780/DDP and COC1/DDP cells incubated with anti-LRP antibody contained more cisplatin than the nuclei of A2780/DDP and COC1/DDP cells not treated with anti-LRP antibody. Efflux of cisplatin was greater from the nuclei of A2780/DDP and COC1/DDP cells than those of A2780 and COC1 cells, and was inhibited by anti-LRP monoclonal antibody. Thus, LRP was involved in the resistance of ovarian cancer cells to cisplatin and has an important role in the transport of cisplatin both in exocytotic vesicles and between the nucleus and cytoplasm.     

Multidrug resistance and the lung resistance-related protein in human colon carcinoma SW-620 cells.

BACKGROUND: Lung resistance-related protein (LRP), the major vault protein in humans, is sometimes overexpressed in multidrug-resistant cells. Because cells transfected with the LRP gene did not express the multidrug-resistant phenotype, we investigated whether LRP is involved in multidrug resistance. METHODS: SW-620 cells, a human colon carcinoma cell line, alone or transfected with an expression vector carrying a LRP-specific ribozyme or with an empty vector, were treated with sodium butyrate to induce differentiation. Expression of P-glycoprotein, multidrug resistance protein, and LRP in the cells was examined by northern and western blotting, and the efflux of doxorubicin in the cells or isolated nuclei was examined by fluorescence microscopy. RESULTS: A 2-week treatment with sodium butyrate induced LRP and conferred resistance to doxorubicin, vincristine, etoposide, gramicidin D, and paclitaxel (Taxol) in SW-620 cells. Insertion of either of two LRP-specific ribozymes into SW-620 cells inhibited these activities. Levels of drugs accumulating in the cells were not decreased by sodium butyrate, suggesting that the adenosine triphosphate-binding cassette transporter is not involved in sodium butyrate-induced multidrug resistance. Doxorubicin was mainly located in the nuclei of untreated cells and in the cytoplasm of sodium butyrate-treated cells. Isolated nuclei from untreated cells or sodium butyrate-treated cells incubated with anti-LRP polyclonal antibodies contained more doxorubicin than the nuclei of sodium butyrate-treated cells alone. Efflux of doxorubicin was greater from the nuclei of sodium butyrate-treated cells than the nuclei of untreated cells or of sodium butyrate-treated cells transfected with a LRP-specific ribozyme and was inhibited by an anti-LRP polyclonal antibody. CONCLUSIONS: LRP is involved in resistance to doxorubicin, vincristine, etoposide, paclitaxel, and gramicidin D and has an important role in the transport of doxorubicin from the nucleus to the cytoplasm.     

多药耐药相关蛋白反义RNA对耐阿霉素人小细胞肺癌细胞株GLC4/ADR耐药性的调节

目的 构建表达多药耐药相关蛋白（MRP）反义RNA的真核表达载体,转染耐药细胞株,初步探讨其影响多药耐药（MDR）的作用机理。方法 以MRPcDNA为模板,应用PCR扩增MRPmRNA5′端（含起始子密码）及MRP mNRA3′端（含终止子密码）片段,通过定向克隆方法,构建表达MRP反义RNA的两个重组载体。通过Lipofectamine将其导入小细胞肺癌（SCLC）耐阿霉素（ADR）的细胞株GLC4／ADR中,经G418筛选,得到分别含pcDNA3空载（MO）、MRP mRNA5′端为靶区的反义RNA（Ma),MRPmRNA3′端为靶区的反义RNA（Mb)的3个细胞克隆。检测细胞内ADR的蓄积改变以及荷瘤裸鼠对ADR的敏感性。结果 经RT－PCR检测,外源片段可获稳定表达。Ma细胞及Mb细胞中,MRP表达分别抑制约14．0％和83．0％,且胞内ADR蓄积量均有一定程度的增加;对ADR的耐药倍数与对照细胞MO相比,分别下降9．5％和28．4％。虽然,MRP反义RNA对细胞的生长、细胞周期及ADR诱导的早期凋亡均无明显影响,但可提高荷瘤裸鼠对ADR的敏感性。结论 MRP反义RNA能抑制MRP蛋白的表达,并使转染细胞内ADR浓度增加,从而逆转MRP介导的MDR。对于配合化疗,提高MRP高表达患者的疗效,具有潜在的应用意义。     

差异凝胶电泳筛选人骨肉瘤细胞多药耐药相关蛋白

摘 要 目的: 应用差异凝胶电泳分析骨肉瘤多药耐药细胞株与亲本细胞株蛋白质表达的差别，筛查骨肉瘤细胞多药耐药相关蛋白。方法：以小剂量多柔比星（doxorubicin, DXR）诱导人骨肉瘤细胞株MG63，建立骨肉瘤多药耐药细胞株MG63/DXR100。以差异凝胶电泳分离两组细胞中的全部蛋白质，应用图像扫描和DeCyder软件分析差异（表达增加或减少>30%）表达的蛋白质点，对其进行质谱鉴定，并在Mascot 数据库中检索。结果：共检测到明显差异表达的蛋白质点30个，选择其中18个点进行质谱鉴定，有5个蛋白质点鉴定成功，它们分别是与肿瘤细胞转移相关的基质金属蛋白酶1（matrix metalloproteinases 1, MMP1）、具有解毒功能的乙醇脱氢酶6（alcohol dehydrogenase 6, ADH6）、属于抑癌基因的FERM域结合蛋白3（FERM domain containing protein 3, FRMD3），以及两个分别由128和300个氨基酸残基构成的未知蛋白。MMP1、ADH6和2种未知蛋白在耐药细胞表达显著高于非耐药细胞组，而FRMD3表达显著显著低于非耐药细胞。结论：通过差异凝胶电泳筛查到，MMP1、ADH6、FRMD3 及2种未知蛋白质在骨肉瘤细胞的多药耐药细胞和非耐药细胞中差异表达，它们可能参与骨肉瘤细胞的多药耐药机制。     

耐药相关蛋白P-gp、MRP、LRP在非小细胞肺癌组织中的表达及意义

Objective： To explore the expression and significance of the multidrug resistance-related proteins P-glycoprotein （P-gp）, multidrug resistance-related protein （MRP）, lung resistance protein （LRP）in human non-small cell lung cancer （NSCLC） tissues and paratumor tissues. Methods： Immunohistochemistry （IHC） was used to examine the expression level of proteins P-gp, MRP and LRP in 43 samples of NSCLC and 15 samples of paratumor tissues. Results： The expression rates of P-gp, MRP and LRP in 43 tumor tissues were 74.42% （32/43）, 67.44% （29/43） and 88.37% （38/43）, respectively, while in 15 paratumor tissues were 13.33% （2/15）, 20.00% （3/15） and 6.67% （1/15）, respectively. There was significant difference in the expression of proteins （P-gp, MRP and LRP） between lung cancer tissues and paratumor tissues （P 〈 0.05）. The expression of proteins P-gp, LRP in lung adenocarcinoma were higher than that in other pathological carcinomas （P 〈 0.05）. The expression of protein MRP was not related to pathological type, clinical stage and classification of histodifferentiation （P 〉 0.05）. Conclusion： Multidrug resistance is more common in NSCLC. The proteins of P-gp, MRP and LRP participated in the formation of multidrug resistance in lung cancer. Detection of multidrug resistance-related proteins in lung cancer tissues may be useful to choice drugs.     

Cytogenetic alterations associated with P-glycoprotein- and non-P-glycoprotein-mediated multidrug resistance in SW-1573 human lung tumor cell lines.

Multidrug resistance can be induced in mammalian cells by selection with a single cytotoxic agent. Overproduction of the energy-dependent drug efflux pump P-glycoprotein, encoded by the mdr1 gene, has been identified as the cause of one form of multidrug resistance. The molecular basis of other forms of multidrug resistance is unknown. Doxorubicin selection of the human squamous lung cancer cell line SW-1573 resulted in multidrug-resistant sublines in which a non-P-glycoprotein-mediated form of multidrug resistance precedes mdr1 expression. Here we present a cytogenetic analysis of both non-P-glycoprotein-mediated multidrug-resistant and P-glycoprotein-mediated multidrug-resistant sublines derived from SW-1573. Three independently derived non-P-glycoprotein-mediated multidrug-resistant sublines showed a heterozygous deletion of the short arm of chromosome 2 (p23-pter), whereas alterations of chromosome 7 were present in the P-glycoprotein-mediated multidrug-resistant cell lines. In one series of clonally derived P-glycoprotein-mediated multidrug-resistant sublines, mdr1 overexpression was accompanied by various markers of chromosome 7 with breakpoints at 7q22, the mdr1 gene being known to be located at 7q21.1. Our data suggest that in SW-1573 cells acquisition of non-P-glycoprotein-mediated multidrug resistance is accompanied by a specific deletion or a translocation involving the short arm of chromosome 2, whereas in the emergence of P-glycoprotein-mediated multidrug resistance a rearrangement of the long arm of chromosome 7 is a critical event.