Overcoming Cancer Resistance Mediated by the Human MDR1 Transporter

抗癌耐药肿瘤是有效癌症治疗的主要障碍。其中之一 肿瘤耐药的主要途径是通过人类多药耐药1(MDR1)反式- Porter，它排出了相对广泛的抗癌药物，并已在~50%的 癌症肿瘤。尽管有大量研究发现，抗癌药物与转运体的相互作用 其分子转运机制目前还不是很清楚。扩大我们的底线- 从MDR1转运抗癌药物的角度来看，迫切需要定义分子和 抗癌药物转运的结构基础。我们在拟议研究中的整体目标是界定 抗癌药物转运的分子机制，鉴定抗癌药物功能基团 与转运蛋白相互作用并精确定位mdr1上的抗癌药物结合位点 传送器。基于已知的小鼠mdr3转运蛋白的X射线晶体结构，中央 假设人多药耐药基因mdr1的抗癌药物转运受多种药物控制 紧密结合在转运蛋白的胞外侧(接近Y953)。从这个中环 假设，提出了两个具体目标：第一个具体目标是确定反病毒的作用机制。 通过MDR1转运肿瘤药物，并检验抗癌药物转运速率为 与抗癌药物结合部位的数量直接相关。第二个具体目标是阻吓- 用原子力显微镜(AFM)挖掘抗癌药物结合的MDR1构象 用核磁共振确定抗癌药物在mdr1上的位置。这些调查已经被取消- 签署以测试具有较高转运率的抗癌药物具有结合位点的假设 相对靠近传输器的胞外侧。最终，成功完成 这些研究将导致识别导致mdr1的特定抗癌药物特性。 中介运输。这一信息将使我们能够设计新的第四代mdr1反式- Porter抑制剂，并对候选和商业化的抗病毒药物进行合理修改 抗癌药物，以最大限度地减少mdr1介导的外排。如果没有完成的新知识 这项研究为合理设计能够有效克服MDR1的药物提供了有效的策略。 介导的癌症耐药性可能仍然有限，而MDR1介导的耐药性将重新 主要是导致癌症耐药性和死亡率的主要原因。

Anti-cancer drug-resistant tumors represent a major impediment to effective cancer therapy. One of the main pathways of cancer resistance is through the human multidrug resistance 1 (MDR1) trans- porter, which effluxes a relatively broad range of anti-cancer drugs and has been identified in ~50% of cancerous tumors. Despite findings from numerous studies, anti-cancer drug-transporter interactions and their molecular transport mechanisms are currently not well understood. To broaden our under- standing of anti-cancer drug transport by MDR1, there is a critical need to define the molecular and structural basis of anti-cancer drug transport. Our overall objective in the proposed studies is to define the molecular mechanisms of anti-cancer drug transport, to identify anti-cancer drug functional groups that interact with the transporter and to pinpoint the anti-cancer drug binding sites on the MDR1 transporter. Based on the known X-ray crystal structure of the mouse mdr3 transporter, the central hypothesis is that the anti-cancer drug transport rate by human MDR1 is controlled by multiple drugs binding in close proximity to the extracellular side of the transporter (near Y953). From this central hypothesis, two specific aims are proposed: The first specific aim is to define the mechanism of anti- cancer drug transport by MDR1 and to test the hypothesis that the anti-cancer drug transport rate is directly related to the number of anti-cancer drug binding sites. The second specific aim is to deter- mine the anti-cancer drug bound MDR1 conformations using atomic force microscopy (AFM) and to pinpoint the locations of anti-cancer drugs on MDR1 by NMR. These investigations have been de- signed to test the hypothesis that anti-cancer drugs with higher transport rates have binding sites relatively close to the extracellular side of the transporter. Ultimately, the successful completion of these studies will lead to the identification of specific anti-cancer drug properties that lead to MDR1- mediated transport. This information will allow us to design of novel fourth generation MDR1 trans- porter inhibitors and to make rational modifications of candidate and commercially available anti- cancer drugs to minimize MDR1-mediated efflux. Without the new knowledge from the completion of this research, effective strategies for rationally designing drugs that can effectively overcome MDR1- mediated cancer resistance are likely to remain limited and MDR1-mediated drug resistance will re- main a leading cause of cancer resistance and mortality.