ATP结合盒转运蛋白介导的肿瘤多药耐药及其逆转剂

肿瘤多药耐药（MDR）是导致肿瘤化疗失败的主要原因之一，是多种复杂机制：共同作用的结果。其中，肿瘤细胞膜上ATP结合盒（ABC）转运蛋白的表达或功能异常是肿瘤细胞产生MDR的重要机制之一。现以P-糖蛋白、多药耐药相关蛋白、乳腺癌耐药蛋白等为例，综述ABC转运蛋白的结构功能、与肿瘤的关系以及MDR逆转剂的研发进展。     

多药耐药相关蛋白-2与肿瘤耐药的研究进展

多药耐药（multidrug resistance，MDR）是导致肿瘤患者化疗失败的主要原因之一。在人类耐药肿瘤细胞中，MDR与多种转运蛋白相关，如P-糖蛋白（P-glyeoprotein，P—gP）、多药耐药相关蛋白家族（multidrug resistance—associated proteins，MRPs）和乳腺癌耐药蛋白（breast cancerr esistance protein，BCRP），这些蛋白都属于ATP结合盒（adenosine triphosphatebinding cassette，ABC）膜转运蛋白超家族。     

microRNAs与ABC转运蛋白介导的肿瘤多药耐药研究进展

目的回顾ABC转运蛋白与肿瘤耐药的研究现状,探讨miRNA在逆转肿瘤耐药过程中的作用机制。方法应用PubMed和CNKI期刊全文数据库检索系统,检索2010-01-01-2014-05-20的相关文献,以"ABC转运蛋白、miRNA和多药耐药"为关键词。纳入标准:1)ABC转运蛋白的表达水平与肿瘤耐药;2)miRNA对ABC转运蛋白表达水平的调控;3)miRNA对肿瘤细胞药物敏感性的影响,根据纳入标准符合分析的文献34篇。结果大多数癌症患者使用一种化疗药物治疗后,肿瘤细胞可能因为种种原因,不仅对该药产生耐药,而且对多种结构不同和作用机制完全不同的其他药物也产生交叉耐药。研究表明,在多药耐药导致肿瘤化疗失败的众多原因中,ABC转运蛋白过表达是导致肿瘤多药耐药的主要原因之一。在耐药肿瘤细胞当中高表达的ABC转运蛋白主要有乳腺癌耐药蛋白ABCG2,多药耐药相关蛋白ABCC1,P-糖蛋白ABCB1,这些蛋白采用ATP水解的能量将细胞内药物泵出细胞外,从而降低细胞内药物的浓度,使细胞产生耐药性。miRNA能与ABC转运蛋白mRNA的3′UTR结合,使mRNA降解或抑制其翻译,导致目标蛋白的表达受到抑制,从而增加肿瘤细胞的药物敏感性,逆转由ABC转运蛋白过表达引起的肿瘤多药耐药。结论 miRNA可以逆转由ABC转运蛋白家族高表达所引起的肿瘤耐药,这为肿瘤多药耐药的研究提供了新的思路。     

转运蛋白及其介导的肿瘤多药耐药研究

 引言 究发现,MDR 的出现与肿瘤细胞内药物聚集降低有关,表明药物转运的改变(外排增加) 可能是产生耐药的原因。参与药物外排机制的膜转运蛋白主要有: P-蛋白( P-qP) 、多药耐药相关蛋白(MRP) 、乳腺癌耐药蛋白(BCRP) ) 和肺耐药蛋白(L RP) 等。前三者同属于A TP 结合盒(adenosinetriphosphate - binding cassette ,ABC) 膜转运蛋白超家族成员[ 1 ] 。药物转运介导的多药耐药是近年来耐药研究领域的一大热点,本文就转运蛋白及其介导的多药耐药研究作一综述。     

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.     

ABCG2介导的多药耐药机制及其逆转

多药耐药(MDR)是肿瘤化疗失败最常见的原因.ABCG2属于ABC转运蛋白超家族的一员,在多种肿瘤细胞中表达,能高效转运多种化疗药物.ABCG2的高表达既是侧群(sP)细胞的标志,又是肿瘤对化疗药物抵抗的重要原因.ABCG2的拮抗剂可在逆转肿瘤MDR中发挥一定作用.     

ABCG2介导的肿瘤多药耐药

ABCG2是ATP结合盒(ABC)转运超家族中的一员,其过表达被认为是限制多种化疗药物在细胞内聚集的重要机制之一.ABCG2底物范围广泛,包括多种抗肿瘤药物和环境致癌物等,与肿瘤的多药耐药(MDR)和肿瘤发展有关.以ABCG2为靶点逆转MDR受到广泛关注.     

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.     

ABC transporters and drug resistance in leukemia: was P-gp nothing but the first head of the Hydra?

More than 30 years ago it was discovered that permeability glycoprotein (P-gp) can cause drug resistance. Over the following decades numerous studies showed that high expression of P-gp is associated with poor prognosis in acute myeloid leukemia in adults and that it causes multidrug resistance via ATP-dependent drug efflux. It was hoped that an inhibition of P-gp could sensitize resistant leukemic cells to chemotherapy and thus improve treatment results. Today we know that the family of ATP-binding cassette transporters (ABC transporters) comprises 48 different proteins. Some of them seem to be able to cause drug resistance as well as P-gp. This review focuses on emerging data on the clinical relevance of other ABC transporters, such as BCRP, MRP3, and ABCA3. When Heracles fought the ancient Hydra, he had to fight all the heads at ones but only one head was vital for the beast. Can we block all the relevant ABC transporters at once? Is there one transporter that is more important than the others?     

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.     

Special AT-rich sequence binding protein 1 promotes multidrug resistance in gastric cancer by regulation of Ezrin to alter subcellular localization of ATP-binding cassette transporters

Multidrug resistance is a primary factor in the poor response to chemotherapy and subsequent death in gastric cancer patients. However, the molecular mechanisms involved remain unclear. In this study, the high expression of special AT-rich sequence binding protein 1 (SATB1) in gastric cancer was found to be associated with reduced sensitivity to various chemotherapy drugs. Our results demonstrate that SATB1 can promote chemotherapy resistance in gastric cancer in vitro and in vivo. SATB1 exerts its effect by enhancing the activity of multiple ATP-binding cassette (ABC) transporters (P-glycoprotein, multidrug resistance-associated protein, and breast cancer resistance protein) in gastric cancer cell lines. We also found that SATB1 affects ABC transporters by altering the subcellular localization of the ABC transporter rather than its expression. Subsequently, we confirmed that Ezrin binds to various ABC transporters and affects their subcellular localization. In addition, we found that SATB1 can also bind to the Ezrin promoter and regulate its expression. In the present study, we elucidate the mechanism of SATB1-mediated multidrug resistance in gastric cancer, providing a basis for SATB1 as a potential target for reversal of resistance.     

The role of ABC transporters in clinical practice

Drug resistance remains one of the primary causes of suboptimal outcomes in cancer therapy. ATP-binding cassette (ABC) transporters are a family of transporter proteins that contribute to drug resistance via ATP-dependent drug efflux pumps. P-glycoprotein (P-gp), encoded by the MDR1 gene, is an ABC transporter normally involved in the excretion of toxins from cells. It also confers resistance to certain chemotherapeutic agents. P-gp is overexpressed at baseline in chemotherapy-resistant tumors, such as colon and kidney cancers, and is upregulated after disease progression following chemotherapy in malignancies such as leukemia and breast cancer. Other transporter proteins mediating drug resistance include those in the multidrug-resistance-associated protein (MRP) family, notably MRP1, and ABCG2. These transporters are also involved in normal physiologic functions. The expressions of MRP family members and ABCG2 have not been well worked out in cancer. Increased drug accumulation and drug resistance reversal with P-gp inhibitors have been well documented in vitro, but only suggested in clinical trials. Limitations in the design of early resistance reversal trials contributed to disappointing results. Despite this, three randomized trials have shown statistically significant benefits with the use of a P-gp inhibitor in combination with chemotherapy. Improved diagnostic techniques aimed at the selection of patients with tumors that express P-gp should result in more successful outcomes. Further optimism is warranted with the advent of potent, nontoxic inhibitors and new treatment strategies, including the combination of new targeted therapies with therapies aimed at the prevention of drug resistance.     

药物转运蛋白和多药耐药性的研究进展

多药耐药性(MDR)是肿瘤化疗失败的最常见原因，药物转运蛋白在肿瘤多药耐药性中产生了重要的作用。这些属于ATP结合盒式转运蛋白的药泵激活导致药物经由细胞膜外排，ABC转运蛋白3个亚家族涉及到细胞毒性药物的转运，这些转运蛋白包括ABCB亚家族、ABCC亚家族和ABCG亚家族。本文就几年来在药物转运蛋白与MDR方面的研究进展作一综述。     

Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma

Pancreatic ductal adenocarcinoma is among the top 10 causes of death from cancer in industrialized countries. In comparison with other gastrointestinal malignancies, pancreatic cancer is one of the tumors most resistant to chemotherapy. An important mechanism of tumor multidrug resistance is increased drug efflux mediated by several transporters of the ABC superfamily. Especially BCRP (ABCG2), MDR1 P-glycoprotein (ABCB1) and members of the MRP (ABCC) family are important in mediating drug resistance. The MRP family consists of 9 members (MRP1-MRP9) with MRP1-MRP6 being best characterized with respect to protein localization and substrate selectivity. Here, we quantified the mRNA expression of BCRP and of all MRP family members in normal human pancreas and pancreatic carcinoma and analyzed the mRNA level of the transporters most abundantly expressed in pancreatic tissue, BCRP, MRP1, MRP3, MRP4 and MRP5, in 37 tissue samples. In addition, we determined the localization of the 4 MRP proteins in normal human pancreas and in pancreatic carcinoma. The expression of BCRP, MRP1 and MRP4 mRNA did not correlate with tumor stage or grading. On the other hand, the expression of MRP3 mRNA was upregulated in pancreatic carcinoma samples and was correlated with tumor grading. The MRP5 mRNA level was significantly higher in pancreatic carcinoma tissue compared to normal pancreatic tissue. These data suggest that MRP3 and MRP5 are involved in drug resistance of pancreatic tumors and that quantitative analysis of their expression may contribute to predict the benefit of chemotherapy in patients with pancreatic cancer.     

Involvement of the Multidrug Resistance Protein 3 in Drug Sensitivity and Its Expression in Human Glioma

The multidrug resistance protein (MRP) family belongs to the ATP-binding cassette superfamily (ABC) of transporters, which are involved in ATP-dependent transport of hydrophobic compounds. One of the MRP family, MRP1 , is partially associated with the multidrug resistance phe-notype in brain tumors. In this study, we asked whether another MRP family gene, MRP3 , could affect drug sensitivity to anticancer agents in human glioma cell lines and clinical glioma specimens. We first produced two antisense transfectants by introduction of antisense MRP3 cDNA into the glioma cell line NHG2, which endogenously expresses MRP3. The two MRP3 antisense transfectants showed 2- to 5-fold increases in drug sensitivity to etoposide and cisplatin compared with NHG2 cells, but their sensitivity to vincristine or nitrosourea was not changed. Two MRP3 cDNA sense transfectants of pig kidney cell lines showed 4- to 6-fold drug resistance to etoposide, but only 1.4- to 1.5-fold to cisplatin. We next compared the mRNA levels of four ABC transporters, multi-drug resistance 1 ( MDR1 ), MRP1, MRP2 and MRP3 in clinical samples, including 34 patients with gliomas, by quantitative RT-PCR analysis. In some of the clinical samples, increased expression of MRP1 and MRP3 was apparent in malignant gliomas. In situ hybridization revealed that glioma cells were stained with MRP3 probe. MRP3 may modulate drug sensitivity to certain anticancer agents in human gliomas.     

Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells

Membrane transporters play important roles in mediating chemosensitivity and -resistance of tumor cells. ABC transporters, such as ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP, are frequently associated with decreased cellular accumulation of anticancer drugs and multidrug resistance of tumors. SLC transporters, such as folate, nucleoside, and amino acid transporters, commonly increase chemosensitivity by mediating the cellular uptake of hydrophilic drugs. Ion channels and pumps variably affect sensitivity to anticancer therapy by modulating viability of tumor cells. A pharmacogenomic approach, using correlations between drug potency and transporter gene expression in multiple cancer cell lines, has shown promise for identifying potential drug-transporter relationships and predicting anticancer drug response, in an effort to optimize chemotherapy for individual patients.