Studies on a Novel Taxane Pump

新型紫杉烷泵的研究

• 批准号: 8132430
• 负责人: ELIZABETH A HOPPER-BORGE
• 金额: $ 15.48万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8132430
• 关键词: ABCB1 gene; ABCC1 gene; ATP Hydrolysis; ATP phosphohydrolase; ATP-Binding Cassette Transporters; Anions; Anthracyclines; Antineoplastic Agents; Binding; Biochemical; Biological Models; Cancer Patient; Carrier Proteins; Cells; Drug Binding Site; Drug Transport; Drug resistance; Effectiveness; Elements; Embryo; Epipodophyllotoxin Compound; Estradiol; Family member; Fibroblasts; Genes; Glucuronides; Glutathione; Goals; Health; Human; Humulus; In Vitro; Knockout Mice; Laboratories; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Membrane; Membrane Transport Proteins; MgATP; Mus; Natural Product Drug; P-Glycoprotein; P-Glycoproteins; Paclitaxel; Pharmaceutical Preparations; Phenotype; Play; Protein Family; Proteins; Publishing; Pump; Research; Resistance; Resistance profile; Role; Serum; Structure-Activity Relationship; System; Taxane Compound; Tissues; Vesicle; Vinca Alkaloids; Wild Type Mouse; Work; chemotherapeutic agent; design; efflux pump; human tissue; in vitro Model; in vivo; in vivo Model; information gathering; inhibitor/antagonist; insight; interest; malignant breast neoplasm; member; mouse model; novel; nucleotide analog; protein function; resistance factors; taxane

DESCRIPTION (provided by applicant): Cellular resistance to chemotherapeutic agents is a major obstacle in the treatment of human cancers. Efflux pumps, specifically P-glycoprotein (Pgp) and multidrug resistance protein (MRP) subfamily members contribute to drug resistance by directly effluxing anticancer drugs from cells. MRP subfamily members transport glucuronidated and glutathione conjugated substrates, and confer resistance to a wide range of agents including anthracyclines, epipodophyllotoxins, vinca alkaloids, and nucleotide analogs. Our laboratory has shown that MRP7 is competent in the transport of amphipathic anions, using membrane vesicles, the MgATP dependent transport of 17 p-estradiol-(17-p-D-glucuronide) (E217BG) was established. Further, our previous work has demonstrated that MRP7 has a resistance phenotype which is distinct from other MRP family members: in that MRP7 is the only member of this group to confer resistance to taxanes. MRP7 is only the second pump to demonstrate this resistance, the first identified pump conferring this resistance is Pgp. Taxanes are used primarily in the treatment of ovarian, lung and breast cancer. To date, all of the functional information gathered about MRP7 has been acquired using in vitro model systems. Since MRP7 has a distinct phenotype and has the lowest homology to MRP1 of all the MRP subfamily members, it is of interest to determine the biochemical parameters which are responsible for its activities. Further, biochemical and structural information that would be critical to the rational design of inhibitors or modulators has not yet been elucidated. This proposal will outline plans to elucidate the role MRP7 plays in the in vivo resistance phenotype of this protein using a knockout mouse model that we developed. The second aim will elucidate the specific biochemical activities that are required for MRP7 unction. For example, the specific biochemical activities related to binding, ATP hydrolysis and modulation of the activities which are involved in MRP7's ability to transport drug. The third aim will characterize the structural elements required for MRP7 function. By using a combination of in vivo and in vitro approaches, these aims will lend insight into this recently discovered resistance factor. It is important to have an understanding of the proteins that lower the effectiveness of chemotherapeutic agents used to treat cancer patients. The goal of this proposal is aimed is to obtain information about one of these recently identified proteins.

描述（申请人提供）：细胞对化疗药物的耐药性是治疗人类癌症的主要障碍。外排泵，特别是P-糖蛋白（Pgp）和多药耐药蛋白（MRP）亚家族成员通过直接从细胞外排抗癌药物而导致耐药性。MRP亚家族成员转运葡萄糖醛酸化和谷胱甘肽缀合的底物，并赋予对包括蒽环类、表鬼臼毒素、长春花生物碱和核苷酸类似物在内的广泛试剂的抗性。我们的实验室已经证明，MRP 7是在两亲性阴离子的运输主管，使用膜囊泡，建立了17 β-雌二醇-（17-β-D-葡萄糖醛酸苷）（E217 BG）的MgATP依赖性转运。此外，我们以前的工作已经证明，MRP 7具有与其他MRP家族成员不同的抗性表型：因为MRP 7是该组中唯一赋予紫杉烷抗性的成员。MRP 7仅是证明该耐药的第二个泵，第一个确定的产生该耐药的泵是Pgp。紫杉烷类药物主要用于治疗卵巢癌、肺癌和乳腺癌。 迄今为止，所有收集到的关于MRP 7的功能信息都是使用体外模型系统获得的。由于MRP 7具有独特的表型，并且在所有MRP亚家族成员中与MRP 1具有最低的同源性，因此确定负责其活性的生化参数是有意义的。此外，尚未阐明对抑制剂或调节剂的合理设计至关重要的生物化学和结构信息。该提案将概述计划，以阐明MRP 7在体内的这种蛋白质的耐药表型使用敲除小鼠模型，我们开发的作用。第二个目标是阐明MRP 7功能所需的特定生化活性。例如，与结合、ATP水解和调节MRP 7转运药物的能力有关的特定生化活性。第三个目标将描述MRP 7功能所需的结构要素。通过使用体内和体外方法的组合，这些目标将有助于深入了解这种最近发现的耐药因素。 重要的是要了解降低用于治疗癌症患者的化疗药物的有效性的蛋白质。该提案的目标是获得有关这些最近鉴定的蛋白质之一的信息。

项目成果

Lapatinib and erlotinib are potent reversal agents for MRP7 (ABCC10)-mediated multidrug resistance.

• DOI: 10.1016/j.bcp.2009.08.021
• 发表时间: 2010-01-15
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Kuang, Ye-Hong;Shen, Tong;Chen, Xiang;Sodani, Kamlesh;Hopper-Borge, Elizabeth;Tiwari, Amit K.;Lee, Jeferson W. K. K.;Fu, Li-Wu;Chen, Zhe-Sheng
• 通讯作者: Chen, Zhe-Sheng

Synthesis and biological evaluation of pentacyclic strychnos alkaloids as selective modulators of the ABCC10 (MRP7) efflux pump.

• DOI: 10.1021/jm501189p
• 发表时间: 2014-12-26
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Teijaro CN;Munagala S;Zhao S;Sirasani G;Kokkonda P;Malofeeva EV;Hopper-Borge E;Andrade RB
• 通讯作者: Andrade RB

Modulation of the ATPase and transport activities of broad-acting multidrug resistance factor ABCC10 (MRP7).

• DOI: 10.1158/0008-5472.can-12-1340
• 发表时间: 2012-12-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Malofeeva EV;Domanitskaya N;Gudima M;Hopper-Borge EA
• 通讯作者: Hopper-Borge EA

Abcc10 status affects mammary tumour growth, metastasis, and docetaxel treatment response.

• DOI: 10.1038/bjc.2014.326
• 发表时间: 2014-08-12
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Domanitskaya, N.;Wangari-Talbot, J.;Jacobs, J.;Peiffer, E.;Mahdaviyeh, Y.;Paulose, C.;Malofeeva, E.;Foster, K.;Cai, K. Q.;Zhou, Y.;Egleston, B.;Hopper-Borge, E.
• 通讯作者: Hopper-Borge, E.