Development of Fourth Generation ABC Inhibitors from Natural Products: A Novel Approach to Overcome Cancer Multidrug Resistance
Development of Fourth Generation ABC Inhibitors from Natural Products: A Novel Approach to Overcome Cancer Multidrug Resistance
复制标题
DOI：
10.2174/1871520615666150113103439
复制
发表时间：
2015-01-01
影响因子：
2.8
通讯作者：
Hoti, Sugeerappa Laxmanappa
中科院分区：
文献类型：
--
作者：
Karthikeyan, Subburayan;Hoti, Sugeerappa Laxmanappa
癌症中因ABC药物转运蛋白过度表达而导致的多药耐药（MDR）是现代化疗的一个主要问题。对MDR的分子研究表明，耐药性是由ABC超家族的各种转运蛋白引起的，其中包括磷酸糖蛋白（P - gp/MDR1/ABCB1）、多药耐药相关蛋白 - 1（MRP1）和乳腺癌耐药蛋白（BCRP）。它们在功能上已被定性，被认为是癌细胞中MDR发展的主要因素。这些依赖ATP的转运蛋白通过减少药物摄取或增加药物从靶细胞器的外排而导致MDR。几种MDR逆转剂正在研发中，并且处于临床试验的不同阶段。前三代ABC调节剂，如奎宁、维拉帕米、环孢素 - A、他立喹达、PSC 833、LY335979和GF120918，需要高剂量给药以逆转MDR，并且伴有不良反应。此外，这些调节剂非选择性地抑制ABC，并使化疗药物在脑和肾中不良蓄积。目前，研究已朝着利用具有化学增敏潜力的天然产物逆转MDR的方向迈进。全球范围内，天然产物具有丰富的生物多样性，可作为药物研发的来源。这些产物可能提供更多具有优越活性的先导化合物，从而为MDR癌细胞开发更有效的疗法。在此，我们简要综述了用于逆转MDR调节剂的天然产物的现状，并讨论了当前临床环境中MDR策略的长期目标。
Multidrug resistance (MDR) in cancer caused due to overexpression of ABC drug transporters is a major problem in modern chemotherapy. Molecular investigations on MDR have revealed that the resistance is due to various transport proteins of the ABC superfamily which include Phosphoglycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated protein-1 (MRP1), and the breast cancer resistance protein (BCRP). They have been characterized functionally and are considered as major players in the development of MDR in cancer cells. These ATP-dependent transporter proteins cause MDR either by decreased uptake of the drug or increased efflux of the drug from the target organelles. Several MDR-reversing agents are being developed and are in various stages of clinical trials. The first three generations of ABC modulators such as quinine, verapamil, cyclosporine-A, tariquitor, PSC 833, LY335979, and GF120918 required to be administered in high doses to reverse MDR and were associated with adverse effects. Additionally, these modulators non-selectively inhibit ABC and adversely accumulate chemotherapeutic drugs in brain and kidney. Currently, research has stepped up towards reversing MDR by using natural products which exhibitted potential as chemosensitizers. Globally, there is a rich biodiversity of natural products which can be sourced for developing drugs. These products may provide more lead compounds with superior activity, foremost to the development of more effective therapies for MDR cancer cells. Here, we briefly review the status of natural products for reversing MDR modulators, and discuss the long term goal of MDR strategies in current clinical settings.