Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents.
Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents.
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DOI：
10.18632/oncotarget.4493
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Chen ZS
中科院分区：
文献类型：
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作者：
Zhang YK;Zhang H;Zhang GN;Wang YJ;Kathawala RJ;Si R;Patel BA;Xu J;Chen ZS
atp结合盒转运体的过度表达导致癌细胞产生多药耐药，导致化疗失败。在体外实验中，我们研究了一对半合成的ocotilol类似物(20S, 24R/S)-环氧-12β， 25-二羟基-多马烷-3β-胺（ORA和OSA）是否能抑制ABCB1转运体。ORA （1 μM和3 μM）可显著逆转ABCB1过表达的SW620/Ad300和HEK/ABCB1细胞对紫杉醇和新碱的耐药性，而OSA无显著影响。此外，ORA （3 μM）通过抑制ABCB1的外排功能，显著增加了[3H]-紫杉醇在细胞内的积累。同时，ORA （3 μM）和OSA （3 μM）均未显著改变ABCB1蛋白的表达水平和亚细胞位置。此外，ABCB1 atp酶研究表明，ORA对atp酶活性的刺激作用比OSA更强。与OSA相比，ORA在ABCB1跨膜结构域内也表现出更高的对接评分。总之，我们得出结论，ORA通过竞争性抑制ABCB1药物外排功能逆转ABCB1介导的MDR。
Overexpression of ATP-Binding Cassette transporters leads to multidrug resistance in cancer cells and results in the failure of chemotherapy. In this in-vitro study, we investigated whether or not (20S, 24R/S)-epoxy-12β, 25-dihydroxy-dommarane-3β-amine (ORA and OSA), a pair of semi-synthetic ocotillol analogue epimers, could inhibit the ABCB1 transporter. ORA (1 μM and 3 μM) significantly reversed the resistance to paclitaxel and vincristine in ABCB1-overexpressing SW620/Ad300 and HEK/ABCB1 cells, whereas OSA had no significant effects. In addition, ORA (3 μM) significantly increased the intracellular accumulation of [3H]-paclitaxel by suppressing the efflux function of ABCB1. Meanwhile, both ORA (3 μM) and OSA (3 μM) did not significantly alter the expression level or the subcellular location of ABCB1 protein. Moreover, the ABCB1 ATPase study suggested that ORA had a stronger stimulatory effect on the ATPase activity than OSA. ORA also exhibited a higher docking score as compared with OSA inside transmembrane domain of ABCB1. Overall, we concluded that ORA reverse ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function.