Liu Teng, Peng Yongbo, Li Xiong, Liu Lian, Liu Fang, He Leye
Department of Infectious Diseases and Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha 410008, PR China.
Molecular Science and Biomedicine Laboratory, College of Life Sciences, State Key Laboratory for Chemo/Bio-Sensing and Chemometrics, Hunan University, Changsha 410082, PR China.
Bioorg Med Chem. 2017 Oct 15;25(20):5461-5467. doi: 10.1016/j.bmc.2017.08.003. Epub 2017 Aug 4.
Multidrug resistance (MDR) limits the application of a large number of cancer-fighting agents in clinical therapy. One reason is that P-glycoprotein (Pgp) efflux pumps are usually overexpressed and lead to drug efflux in the cancer cells, which limits the viability of many chemotherapeutics. Current available inhibitors which block the Pgp pump efflux are usually not widely used in clinical practice, because they change other drug pharmacokinetic profiles or increase side effects. Here, through covalent linkage of cancer-targeting delocalized lipophilic cation FF and DNA-damaging drug nitrogen mustard chlorambucil (CLB), we rationally designed and synthesized a tumor-targeting anticancer agent FFCLB. And we found and proved that the FFCLB was capable of reducing the outflow of Pgp substrates efficiently. This conjugate selectively improves adriamycin uptake and toxicity through reducing MDR1 mRNA and Pgp protein expression. Based on molecular targeted strategy, this study can facilitate the discovery of superior MDR reducing agents to provide a more effective and safer way of resensitizing MDR.
多药耐药性（MDR）限制了大量抗癌药物在临床治疗中的应用。一个原因是P-糖蛋白（Pgp）外排泵通常过度表达，导致癌细胞中的药物外排，这限制了许多化疗药物的有效性。目前可用的阻断Pgp泵外排的抑制剂通常未在临床实践中广泛使用，因为它们会改变其他药物的药代动力学特征或增加副作用。在此，通过将靶向癌症的离域亲脂性阳离子FF与DNA损伤药物氮芥苯丁酸氮芥（CLB）共价连接，我们合理设计并合成了一种靶向肿瘤的抗癌剂FFCLB。并且我们发现并证明FFCLB能够有效减少Pgp底物的流出。这种缀合物通过降低MDR1 mRNA和Pgp蛋白表达，选择性地提高阿霉素的摄取和毒性。基于分子靶向策略，本研究有助于发现更优异的多药耐药性降低剂，以提供一种更有效、更安全的使多药耐药性重新敏感化的方法。
