Alkyl-lysophospholipid resistance in multi drug-resistant Leishmania tropica and chemosensitization by a novel P-glycoprotein-like transporter modulator
Alkyl-lysophospholipid resistance in multi drug-resistant Leishmania tropica and chemosensitization by a novel P-glycoprotein-like transporter modulator
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DOI：
10.1128/aac.45.9.2468-2474.2001
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发表时间：
2001-09-01
影响因子：
4.9
通讯作者：
Gamarro, F
中科院分区：
文献类型：
--
作者：
Pérez-Victoria, JM;Pérez-Victoria, FJ;Gamarro, F
抗药性已成为治疗利什曼病的主要障碍。烷基溶血磷脂（alkyllysophospholipids，ALP）是最有前途的抗利什曼病药物，最初是作为抗肿瘤药物开发的。为了预测在不久的将来可能出现的临床失败，我们研究了利什曼原虫对这些药物耐药的可能机制。这里提出的结果支持参与的ATP结合盒（ABC）超家族的成员，利什曼原虫P-糖蛋白样转运蛋白，在耐碱性磷酸酶。(i)首先，一个多药耐药（MDR）热带利什曼原虫线过表达的P-糖蛋白样转运蛋白显示出显着的交叉耐药性的ALP米替福新和edelfosine，耐药指数分别为9.2和7.1倍。(ii)MDR细胞系中P-糖蛋白表达的降低与ALP抗性的显著降低相关。(iii)ALP能够调节P-糖蛋白介导的MDR细胞对柔红霉素的抗性。(iv)我们已经发现了一种新的这种转运蛋白的抑制剂，倍半萜烯C-3，完全敏感MDR寄生虫ALP。(v)最后，MDR系表现出比bodipy-C-5-PC（磷脂酰胆碱的荧光类似物，具有类似于依地福新的结构）的野生型系更低的积累。此外，C-3显着增加的荧光类似物的积累水平类似于野生型寄生虫。利什曼原虫P-糖蛋白样转运蛋白对治疗利什曼病的药物的耐药性的参与也支持了开发这种ABC转运蛋白的新的特异性抑制剂的重要性。
Drug resistance has emerged as a major impediment in the treatment of leishmaniasis. Alkyl-lysophospholipids (ALP), originally developed as anticancer drugs, are considered to be the most promising antileishmanial agents. In order to anticipate probable clinical failure in the near future, we have investigated possible mechanisms of resistance to these drugs in Leishmania spp. The results presented here support the involvement of a member of the ATP-binding cassette (ABC) superfamily, the Leishmania P-glyco protein-like transporter, in the resistance to ALP. (i) First, a multidrug resistance (MDR) Leishmania tropica line overexpressing a P-glycoprotein-like transporter displays significant cross-resistance to the ALP miltefosine and edelfosine, with resistant indices of 9.2- and 7.1-fold, respectively. (ii) Reduced expression of P-glycoprotein in the MDR line correlates with a significant decrease in ALP resistance. (iii) The ALP were able to modulate the P-glycoprotein-mediated resistance to daunomycin in the MDR line. (iv) We have found a new Inhibitor of this transporter, the sesquiterpene C-3, that completely sensitizes MDR parasites to ALP. (v) Finally, the MDR line exhibits a lower accumulation than the wild-type line of bodipy-C-5-PC, a fluorescent analogue of phosphatidylcholine that has a structure resembling that of edelfosine. Also, C-3 significantly increases the accumulation of the fluorescent analogue to levels similar to those of wild-type parasites. The involvement of the Leishmania P-glycoprotein-like transporter in resistance to drugs used in the treatment of leishmaniasis also supports the importance of developing new specific inhibitors of this ABC transporter.