Department of Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, China; West China Hospital, Sichuan University, Chengdu, 610041, China.
Wendeng Hospital of Traditional Chinese Orthopedics and Traumatology of Shandong Provice, Wendeng, 264400, China.
Biomed Pharmacother. 2017 Dec;96:659-666. doi: 10.1016/j.biopha.2017.10.041. Epub 2017 Nov 6.
Nowadays, lung cancer, as a health problem in worldwide, has high mortality both in men and women. Despite advances in diagnosis and surgical techniques of lung cancer in recent decades, chemotherapy is still a fundamentally and extensively useful strategy. Vinca alkaloids are a class of important and widely used drugs in the treatment of lung cancer, targeting on the Vinca binding site at the exterior of microtubule plus ends. Either intrinsic or acquired resistance to chemotherapy of Vinca alkaloids has been a major obstacle to the treatment of lung cancer, which arose great interests in studies of understanding and overcoming resistance. In this review, we focused on the application and resistance mechanisms of the Vinca alkaloids such as vinblastine, vincristine, vinorelbine and vinflunine in lung cancer. We reviewed characteristic resistance mechanisms in lung cancer including over-expression of ATP-binding cassette (ABC) transporters P-glycoprotein and structural, functional or expression alterations of β-tubulin (βII, βIII, βIV) which may devote to the development of acquired resistance to the Vinca alkaloids; multidrug-resistance proteins (MRP1, MRP2, MRP3) and RLIP76 protein have also been identified that probably play a significant role in intrinsic resistance. Lung resistance-related protein (LRP) is contributed to lung cancer therapy resistance, but is not deal with the Vinca alkaloids resistance in lung cancer. Understanding the principle of the Vinca alkaloids in clinical application and mechanisms of drug resistance will support individualized lung cancer therapy and improve future therapies.
如今，肺癌作为一个全球性的健康问题，无论在男性还是女性中，其死亡率都很高。尽管近几十年来在肺癌的诊断和手术技术方面取得了进展，但化疗仍然是一种基本且广泛有用的策略。长春碱类是一类在治疗肺癌中非常重要且广泛使用的药物，作用靶点是微管末端外侧的长春碱结合部位。长春碱类药物的内在或获得性耐药性一直是肺癌治疗的主要障碍，这引起了人们对理解和克服耐药性的研究的极大兴趣。在这篇综述中，我们重点介绍了长春碱类药物（如长春碱、长春新碱、长春瑞滨和长春氟宁）在肺癌中的应用和耐药机制。我们综述了肺癌中特征性的耐药机制，包括 ABC 转运蛋白 P-糖蛋白的过度表达以及β-微管蛋白（βII、βIII、βIV）的结构、功能或表达改变，这些可能导致对长春碱类药物的获得性耐药；多药耐药蛋白（MRP1、MRP2、MRP3）和 RLIP76 蛋白也已被确定可能在内在耐药中发挥重要作用。肺耐药相关蛋白（LRP）有助于肺癌治疗耐药，但与肺癌中长春碱类药物耐药无关。了解长春碱类药物在临床应用中的原理和耐药机制将支持个体化肺癌治疗，并改善未来的治疗方法。
