Reversal of p-glycoprotein-mediated multidrug resistance by macrocyclic bisbibenzyl derivatives in adriamycin-resistant human myelogenous leukemia (K562/A02) cells
Reversal of p-glycoprotein-mediated multidrug resistance by macrocyclic bisbibenzyl derivatives in adriamycin-resistant human myelogenous leukemia (K562/A02) cells
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大环双苄基衍生物逆转阿霉素耐药人骨髓性白血病（K562/A02）细胞中p-糖蛋白介导的多药耐药性
DOI：
10.1016/j.tiv.2008.09.015
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发表时间：
2009-02-01
影响因子：
3.2
通讯作者：
Lou, Hong-Xiang
中科院分区：
文献类型：
--
作者：
Li, Xia;Sun, Bin;Lou, Hong-Xiang
大环双联苄是一类源自地钱的特征性天然分子，具有多种生物学意义。 DiHydroptychantol A (DHA) 被鉴定为来自苔类 Asterella angusta 的抗真菌活性大环双联苄。为了了解该化合物的其他生物活性，化学合成的 DHA 及其类似物（化合物 1-3）被用来通过使用阿霉素耐药 K562/A02 细胞来测试这种可能性。通过MTT测定，在测试的化合物(1-4)DHA中，显示出最强的增加阿霉素对K562/A02细胞的细胞毒性的效力，其逆转倍数为8.18(20μM)。进一步研究了 DHA 对 p-糖蛋白 (P-gp) 介导的多药耐药性 (MDR) 的作用机制。基于流式细胞术，我们检测到暴露于不同浓度DHA的K562/A02细胞中阿霉素和罗丹明123的积累显着增加，同时还观察到罗丹明123外流显着减少，这表明DHA导致P-gp活性下降。此外，通过流式细胞术和RT-PCR分析P-gp表达。在用 DHA 预处理 24 小时的 K562/A02 细胞中测量了 P-gp 表达的剂量依赖性减少。在亲本 K562 细胞中未发现此类结果。这些结果表明DHA通过抑制P-gp功能和表达途径阻断药物的排出，从而有效逆转MDR。 (C) 2008 Elsevier Ltd. 保留所有权利。
Macrocyclic bisbibenzyls, a class of characteristic natural molecules derived from liverworts, have diverse biological significances. Dihydroptychantol A (DHA) was identified to be an antifungal active macrocyclic bisbibenzyl from liverwort Asterella angusta. In an attempt to understand other biological activities of this compound, the chemical synthesized DHA and its analogues (compounds 1-3) were employed to test this possibility by using adriamycin-resistant K562/A02 cells. Among the tested compounds (1-4) DHA, showed the strongest potency to increase adriamycin cytotoxicity toward K562/A02 cells by MTT assays and its reversal fold is 8.18 (20 mu M). Mechanisms of DHA on p-glycoprotein (P-gp)-mediated multidrug resistance (MDR) were further investigated. Based on the flow cytometry, we detected the significant increase of adriamycin and rhodamine 123 accumulation in K562/A02 cells exposed to various concentrations of DHA, meanwhile, notable decrease of rhodamine-123 efflux was also observed which revealed, DHA caused a decline of P-gp activity. Furthermore, P-gp expression was analyzed by the flow cytometry and RT-PCR. Dose-dependent reduction of P-gp expression was measured in K562/A02 cells pretreated with DHA for 24 h. No such results were found in parental K562 cells. These results demonstrated DHA reversed effectively MDR by blocking the drugs to be pumped Out Via inhibiting P-gp function and expression pathway. (C) 2008 Elsevier Ltd. All rights reserved.