介导肿瘤多药耐药的ATP结合盒转运体的研究进展

多药耐药（MDR）是阻碍肿瘤化疗成功的一大障碍,其机制之一就是耐药的肿瘤细胞高表达三磷酸腺苷（ATP）结合盒（ABC）转运体。依据此机制提出克服肿瘤细胞耐药的策略即开发外排转运体抑制剂,以期逆转MDR。最近的研究发现肿瘤干细胞也可能是通过表达外排转运体天然耐药,这就提供了一个新的抗癌药物作用靶点。对介导肿瘤细胞多药耐药的ABC转运体及其抑制剂的开发作一综述。     

介导肿瘤多药耐药的ATP结合盒转运体的研究进展

多药耐药（MDR）是阻碍肿瘤化疗成功的一大障碍,其机制之一就是耐药的肿瘤细胞高表达三磷酸腺苷（ATP）结合盒（ABC）转运体。依据此机制提出克服肿瘤细胞耐药的策略即开发外排转运体抑制剂,以期逆转MDR。最近的研究发现肿瘤干细胞也可能是通过表达外排转运体天然耐药,这就提供了一个新的抗癌药物作用靶点。对介导肿瘤细胞多药耐药的ABC转运体及其抑制剂的开发作一综述。     

外排型转运体与肿瘤多药耐药

肿瘤多药耐药（MDR）是导致肿瘤化疗失败的主要原因之一。肿瘤MDR的机制有多种,其中外排型转运体的过表达是导致MDR的主要机制,因此研究外排型转运体介导的肿瘤MDR机制和发现可以逆转肿瘤MDR的抑制剂成为国内外研究的热点。就目前研究的3种三磷酸腺苷结合盒转运体：P-糖蛋白、多药耐药相关蛋白、乳腺癌耐药蛋白介导的MDR及逆转MDR的机制进行综述,以期为提高肿瘤治疗疗效提供依据。     

乳腺癌耐药蛋白BCRP在肿瘤化疗耐药中的研究进展

ABCG2(三磷酸腺苷(ATP)结合转运蛋白G超家族成员2)是ABC转运体(三磷酸腺苷结合盒转运体)超家族中的一员，因其介导肿瘤药物的化疗耐药中而为人们所熟知。自1998年克隆出ABC转运体家族的多药耐药蛋白(ABCG2/BCRP)后，有关于BCRP的研究论文已超过五千多篇。ABC转运体超家族成员均能引起药物耐药。本文主要对ABCG2的结构、功能、与其有关的底物药、抑制剂以及其对肿瘤药物耐药作用进行综述。     

ATP结合盒转运蛋白介导的MDR逆转剂的实验研究现况

多药耐药性(mu ltidrug resistance,MDR)是指人肿瘤细胞对结构各异的化疗药物产生交叉耐药,是肿瘤化疗失败的主要原因之一。为了增强肿瘤细胞对化疗药物的敏感性,积极寻求有效逆转MDR的药物已成为研究重点。体外被证实具有逆转耐药活性的化合物很多,但由于体内要达到体外逆转试验的有效浓度所需剂量过大,毒副作用大,因此限制了临床应用。ATP结合盒转运蛋白家族(ATP-b ind ing cassette,ABC)介导的药物外排机制是目前MDR的主要机制,ABC转运蛋白家族中与多药耐药性相关的转运蛋有P-糖蛋白(P-gp)、多药耐药相关蛋白(MRP)和乳腺癌耐药蛋白(BCRP)。本文对ABC转运蛋白介导的MDR逆转剂的研究进展做一综述。     

P-糖蛋白介导的肿瘤多药耐药与逆转

最近数十年,一些ATP依赖的药物外排泵被证实与肿瘤的多药耐药（MDR）有关。ATP结合盒（ATP—binding cassette,ABC）蛋白是一个结合蛋白大家族,由ABC基因编码,在真核生物和原核生物中都有表达。     

孕烷X受体与肿瘤多药耐药

多药耐药（MDR）是肿瘤化疗失败的主要原因之一。MDR的产生主要由ATP结合盒（ABC）转运蛋白超家族的跨膜蛋白所引起,其中P-糖蛋白及其编码基因mdr1的过表达是MDR产生的最主要机制。研究MDR的产生机制,寻找诱发mdr1表达的诱因并阻断其表达,是克服肿瘤多药耐药性行之有效的方法。近来研究发现,孕烷X受体（PXR）可介导mdr1的表达,活化的PXR诱导MDR1的表达。因此,特异性地阻断PXR的活化可抑制mdr1的表达,从而克服多药耐药性。现已发现多种物质可作为PXR抑制剂或拮抗剂。本文即对核受体PXR与MDR、PXR抑制剂及拮抗剂的研究现状做一介绍,以期为克服肿瘤多药耐药提供参考。     

三阴性乳腺癌化疗抗性机制及治疗策略的研究进展

三阴性乳腺癌（TNBC）是一类雌激素受体、孕激素受体和人表皮生长因子受体表达均阴性的亚型乳腺癌,易复发转移,侵袭性强以及预后较差。化疗已成为TNBC治疗的首选方案,鉴于TNBC本身对化疗产生抵抗导致临床治疗失败,TNBC化疗耐药成为研究热点。化疗抵抗机制主要包括肿瘤干细胞的诱导、ATP结合盒转运体、缺氧与凋亡逃避、表皮生长因子受体、转化生长因子-β通路、Notch通路、Wnt/β-连环蛋白通路、Hedgehog通路等。此外,TNBC患者的疗效和预后获益于近年开展的新辅助化疗、靶向治疗、铂类联合方案、免疫治疗以及新兴疗法。     

肝癌MDR产生途径与逆转研究进展

肝细胞癌（hepatocellular carcinoma,HCC）是世界范围高发恶性肿瘤,治疗手段有手术、放疗和介入化疗,中晚期患者常用化疗,但效果较差.肿瘤细胞多药耐药（multidrug resistance,MDR）是肝癌化疗失败的根本原因,并影响肿瘤转移和复发,最终导致患者死亡.因此,肝癌MDR产生途径及逆转一直是国内外肿瘤界的研究热点,笔者就其进展综述如下。     

P-糖蛋白介导的多药耐药及其逆转剂的研究进展

多药耐药(multidrug resistance,MDR)[1]是指肿瘤细胞对1种抗肿瘤药物产生耐药性的同时,对结构和作用机制完全不同的其他多种抗肿瘤药物产生交叉耐药性,是一种独特的广谱耐药现象[2].MDR由多种途径诱导,可分为经典和非经典MDR两大机制.MDR是肿瘤化疗的一个主要的障碍.抗肿瘤药物在肿瘤细胞积累的下降,可被几种膜蛋白质调节,这些膜蛋白质属于ATP结合的盒式(ATP binding cassette,ABC)运输蛋白家族成员,P-糖蛋白(P-gp)属于这个蛋白家族.P-gp是一种ATP依赖性的跨膜外流泵,它可通过细胞膜转运多种抗肿瘤药,从而限制这些抗肿瘤药进入细胞而导致肿瘤细胞耐药.据此,研究学者着力于寻找抑制P-gp的分子,以逆转肿瘤化疗药的耐药性.近年来由于中药资源丰富,作用靶点多,可针对MDR机制复杂的特点,有学者开始开发逆转肿瘤MDR的中药.     

Revisiting the ABCs of multidrug resistance in cancer chemotherapy

The adenosine tri-phosphate binding cassette (ABC) transporters are one of the largest transmembrane gene families in humans. The ABC transporters are present in a number of tissues, providing protection against xenobiotics and certain endogenous molecules. Unfortunately, their presence produces suboptimal chemotherapeutic outcomes in cancer patient tumor cells. It is well established that they actively efflux antineoplastic agents from cancer cells, producing the multidrug resistance (MDR) phenotype. The inadequate response to chemotherapy and subsequent poor prognosis in cancer patients can be in part the result of the clinical overexpression of ABC transporters. In fact, one of the targeted approaches for overcoming MDR in cancer cells is that directed towards blocking or inhibiting ABC transporters. Indeed, for almost three decades, research has been conducted to overcome MDR through pharmacological inhibition of ABC transporters with limited clinical success. Therefore, contemporary strategies to identify or to synthesize selective "resensitizers" of ABC transporters with limited nonspecific toxicity have been undertaken. Innovative approaches en route to understanding specific biochemical role of ABC transporters in MDR and tumorigenesis will prove essential to direct our knowledge towards more effective targeted therapies. This review briefly discusses the current knowledge regarding the clinical involvement of ABC transporters in MDR to antineoplastic drugs and highlights approaches undertaken so far to overcome ABC transporter-mediated MDR in cancer.     

Reversing agents for ATP-binding cassette (ABC) transporters: application in modulating multidrug resistance (MDR)

One of the main reasons for the failure in cancer chemotherapy is the existence of multidrug resistance (MDR) mechanisms. One form of MDR phenotype is contributed by a group of plasma membrane proteins that belong to a large superfamily of proteins called the ATP-binding cassette (ABC) transporters. There has been intense search for compounds, which can act at reversing MDR phenotype exhibited by ABC transporters such as P-glycoprotein (P-gp), multidrug-resistance protein (MRP) and breast cancer resistance protein (BCRP). Reversing agents can be designed to target MDR-associated ABC transporters at three levels - the protein, mRNA or DNA level. This review aims at describing, over-viewing and discussing currently known MDR reversing agents, which have been shown to act at either of the three levels against ABC transporters. Other potential agents and strategies, which can be used to reverse the MDR phenotype, are also discussed.     

黄酮类化合物对肿瘤多药耐药调节作用的研究进展

多药耐药是临床上化疗失败的重要原因之一。黄酮类化合物存在于多种植物中,具有广泛的药理活性,对P-糖蛋白(P-gp)、多药耐药相关蛋白(MRP)、乳腺癌耐药蛋白(BCRP)等外向转运蛋白的抑制作用使其可能成为肿瘤多药耐药调节剂。文中分别对黄酮类化合物对ABC家族转运蛋白抑制作用的研究概况、作用机制以及构效关系进行综述,为肿瘤多药耐药抑制剂的开发和应用提供重要信息。     

Advances in the molecular detection of ABC transporters involved in multidrug resistance in cancer

ATP-Binding Cassette (ABC) transporters are important mediators of multidrug resistance (MDR) in patients with cancer. Although their role in MDR has been extensively studied in vitro, their value in predicting response to chemotherapy has yet to be fully determined. Establishing a molecular diagnostic assay dedicated to the quantitation of ABC transporter genes is therefore critical to investigate their involvement in clinical MDR. In this article, we provide an overview of the methodologies that have been applied to analyze the mRNA expression levels of ABC transporters, by describing the technology, its pros and cons, and the experimental protocols that have been followed. We also discuss recent studies performed in our laboratory that assess the ability of the currently available high-throughput gene expression profiling platforms to discriminate between highly homologous genes. This work led to the conclusion that high-throughput TaqMan-based qRT-PCR platforms provide standardized clinical assays for the molecular detection of ABC transporters and other families of highly homologous MDR-linked genes encoding, for example, the uptake transporters (solute carriers-SLCs) and the phase I and II metabolism enzymes.     

Multidrug resistance: retrospect and prospects in anti-cancer drug treatment

Conventional cancer chemotherapy is seriously limited by the multidrug resistance (MDR) commonly exhibited by tumour cells. One mechanism by which a living cell can achieve multiple resistances is via the active efflux of a broad range of anticancer drugs through the cellular membrane by MDR proteins. Such drugs are exported in both ATP-dependent and -independent manners, and can occur despite considerable concentration gradients. To the ATP-dependent group belongs the ATP-binding cassette (ABC) transporter family, which includes P-gp, MRP, BCRP, etc. Another protein related to MDR, though not belonging to the ABC transporter family, is lung resistance-related protein (LRP). All of these proteins are involved in diverse physiological processes, and are responsible for the uptake and efflux of a multitude of substances from cancer cells. Many inhibitors of MDR transporters have been identified over the years. Firstly, MDR drugs were not specifically developed for inhibiting MDR; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. They included compounds of diverse structure and function, such as verapamil and cyclosporine, and caused side effects. Secondly, the new drugs were more inhibitor-specific, in terms of MDR transport, and were designed to reduce such side effects (e.g., R-verapamil, dexniguldipine, etc.). Unfortunately, they displayed poor response in clinical studies. Recently, new compounds obtained from drug development programs conducted by the pharmaceutical industry are characterized by a high affinity to MDR transporters and are efficient at nanomolar concentrations. Some of these compounds (e.g., MS-209) are currently under clinical trials for specific forms of advanced cancers. We aim to provide an overview of the properties associated with those mammalian MDR transporters known to mediate significant transport of relevant drugs in cancer treatments. We also summarize recent advances concerning resistance to cancer drug therapies with respect to the function and overexpression of ABC and LRP multidrug transporters.     

Investigational ABC transporter inhibitors

INTRODUCTION: Multidrug resistance (MDR) is the main cause of failure in cancer therapy. One mechanism responsible for MDR is the active efflux of drugs by ATP-binding cassette (ABC) transporters. Several agents have been developed to block transporter-mediated drug efflux and some of these compounds have entered Phase II/III clinical testing. Evidence is also emerging of the role played by ABC transporters in cancer cell signalling that is likely to be important in disease progression and which is distinct from MDR. AREAS COVERED: This article reviews current literature to analyse the rationale for targeting ABC transporters in cancer. Preclinical and clinical results of ABC transporter inhibitors in early clinical trials, as single agents or in combination with other drugs, are described. The development of new strategies to target MDR and the emerging roles of ABC transporters in cancer signalling are discussed. EXPERT OPINION: The intense active search for safe and effective inhibitors of ABC transporters has led to some success in MDR reversal in preclinical studies. However, there has been little impact on clinical outcome. The discovery of novel, potent and nontoxic inhibitors as well as new treatment strategies is therefore needed.     

Development of inhibitors of ATP-binding cassette drug transporters: present status and challenges

BACKGROUND: Multi-drug resistance (MDR) of cancer cells is an obstacle to effective chemotherapy of cancer. The ATP-binding cassette (ABC) transporters, including P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2, play an important role in the development of this resistance. An attractive approach to overcoming MDR is the inhibition of the pumping action of these transporters. Several inhibitors/modulators of ABC transporters have been developed, but cytotoxic effects and adverse pharmacokinetics have prohibited their use. The ongoing search for such inhibitors/modulators that can be applied in the clinic has led to three generations of compounds. The most recent inhibitors are more potent and less toxic than first-generation compounds, yet some are still prone to adverse effects, poor solubility and unfavorable changes in the pharmacokinetics of the anticancer drugs. OBJECTIVE: This review provides an update of the published work on the development of potent modulators to overcome MDR in cancer cells, their present status in clinical studies and suggestions for further improvement to obtain better inhibitors. METHODS: This review summarizes recent advances in the development of less toxic modulators, including small molecules and natural products. In addition, a brief overview of other novel approaches that can be used to inhibit ABC drug transporters mediating MDR has also been provided. CONCLUSION: The multifactorial nature of MDR indicates that it may be important to develop modulators that can simultaneously inhibit both the function of the drug transporters and key signaling pathways, which are responsible for development of this phenomenon.