Di Pietro A, Conseil G, Pérez-Victoria J M, Dayan G, Baubichon-Cortay H, Trompier D, Steinfels E, Jault J M, de Wet H, Maitrejean M, Comte G, Boumendjel A, Mariotte A M, Dumontet C, McIntosh D B, Goffeau A, Castanys S, Gamarro F, Barron D
Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS/Université Claude Bernard-Lyon I, Passage du Vercors, Lyon, France.
Cell Mol Life Sci. 2002 Feb;59(2):307-22. doi: 10.1007/s00018-002-8424-8.
Cancer cell resistance to chemotherapy is often mediated by overexpression of P-glycoprotein, a plasma membrane ABC (ATP-binding cassette) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. P-glycoprotein (ABCB1, according to the human gene nomenclature committee) consists of two homologous halves each containing a transmembrane domain (TMD) involved in drug binding and efflux, and a cytosolic nucleotide-binding domain (NBD) involved in ATP binding and hydrolysis, with an overall (TMD-NBD)2 domain topology. Homologous ABC multidrug transporters, from the same ABCB family, are found in many species such as Plasmodiumfalciparum and Leishmania spp. protozoa, where they induce resistance to antiparasitic drugs. In yeasts, some ABC transporters involved in resistance to fungicides, such as Saccharomyces cerevisiae Pdr5p and Snq2p, display a different (NBD-TMD)2 domain topology and are classified in another family, ABCG. Much effort has been spent to modulate multidrug resistance in the different species by using specific inhibitors, but generally with little success due to additional cellular targets and/or extrusion of the potential inhibitors. This review shows that due to similarities in function and maybe in three-dimensional organization of the different transporters, common potential modulators have been found. An in vitro 'rational screening' was performed among the large flavonoid family using a four-step procedure: (i) direct binding to purified recombinant cytosolic NBD and/or full-length transporter, (ii) inhibition of ATP hydrolysis and energy-dependent drug interaction with transporter-enriched membranes, (iii) inhibition of cell transporter activity monitored by flow cytometry and (iv) chemosensitization of cell growth. The results indicate that prenylated flavonoids bind with high affinity, and strongly inhibit drug interaction and nucleotide hydrolysis. As such, they constitute promising potential modulators of multidrug resistance.
癌细胞对化疗的耐药性通常由P-糖蛋白的过表达介导，P-糖蛋白是一种质膜ABC（ATP结合盒）转运蛋白，它以ATP水解为代价排出细胞毒性药物。根据人类基因命名委员会的规定，P-糖蛋白（ABCB1）由两个同源部分组成，每个部分都包含一个参与药物结合和外排的跨膜结构域（TMD），以及一个参与ATP结合和水解的胞质核苷酸结合结构域（NBD），具有整体的（TMD-NBD）2结构域拓扑结构。来自同一ABCB家族的同源ABC多药转运蛋白存在于许多物种中，如恶性疟原虫和利什曼原虫等原生动物，它们会诱导对抗寄生虫药物产生耐药性。在酵母中，一些参与抗真菌剂耐药性的ABC转运蛋白，如酿酒酵母Pdr5p和Snq2p，具有不同的（NBD-TMD）2结构域拓扑结构，并被归类于另一个家族ABCG。人们花费了大量精力通过使用特异性抑制剂来调节不同物种中的多药耐药性，但由于存在其他细胞靶点和/或潜在抑制剂的外排，通常收效甚微。本综述表明，由于不同转运蛋白在功能上以及可能在三维结构上存在相似性，已发现了共同的潜在调节剂。使用四步法在大型黄酮类化合物家族中进行了体外“理性筛选”：（i）与纯化的重组胞质NBD和/或全长转运蛋白直接结合，（ii）抑制ATP水解以及能量依赖性药物与富含转运蛋白的膜的相互作用，（iii）通过流式细胞术监测细胞转运蛋白活性的抑制，以及（iv）细胞生长的化学增敏作用。结果表明，异戊烯基化黄酮类化合物具有高亲和力结合，并强烈抑制药物相互作用和核苷酸水解。因此，它们构成了有前景的多药耐药性潜在调节剂。
