Swietephragmin D, a limonoid from Swietenia mahagoni, reverses multidrug resistance by inhibiting P-glycoprotein dependent efflux
Swietephragmin D, a limonoid from Swietenia mahagoni, reverses multidrug resistance by inhibiting P-glycoprotein dependent efflux
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DOI：
10.1016/j.phyplu.2022.100266
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发表时间：
2022-03
影响因子：
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通讯作者：
Han Guo;Sheng Gao;Yifan Zhu;Yuanqiang Guo;Zheng Hou;Yonggang Ma
中科院分区：
文献类型：
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作者：
Han Guo;Sheng Gao;Yifan Zhu;Yuanqiang Guo;Zheng Hou;Yonggang Ma
背景：P-糖蛋白介导的外排导致肿瘤细胞产生多药耐药，是化疗失败的重要原因。因此，抑制P-gp是逆转多药耐药的有效途径。 目的： Swietephragmin D是从Swietenia mahagoni (L.) Jacq.的果实和叶子中分离出来的柠檬苦素类化合物。本研究检测了swietephragmin D的逆转效率。 方法：采用罗丹明123外排法测定swietephragmin D的抑制效率。 细胞毒性试验用于测量 swietephragmin D 的逆转作用。进行实时 PCR 和 ATPase 检测以探索逆转机制。结果： Swietephragmin D 以剂量和时间依赖性方式抑制 P-糖蛋白诱导的外流。该化合物比维拉帕米更有效地抑制 P-糖蛋白。 swietephragmin D显着降低多重耐药细胞的IC50值。 ABCB1（编码的 P-糖蛋白）的转录水平不受 swietephragmin D 的影响。然而，swietephragmin D 会刺激 P-糖蛋白的 ATPase 活性。结论：Swietephragmin D 是 P-糖蛋白的底物，抑制 P-gp 介导的外排。它不干扰 ABCB1 的表达。因此，swietephragmin D 作为 P-糖蛋白的竞争性抑制剂逆转了多药耐药性。
Background: P-glycoprotein mediated efflux leads to multidrug resistance of tumor cells, which is an important reason for chemotherapy failure. Thus inhibiting P-gp is an effective approach to reverse multidrug resistance.Purpose: Swietephragmin D is a limonoid compound isolated from the fruits and leaves of Swietenia mahagoni (L.) Jacq.. The reversal efficiency of swietephragmin D was examined in this study.Methods: Rhodamine 123 efflux assays were used to measure inhibition efficiency of swietephragmin D. Cytotoxicity assays were used to measure the reversal effect of swietephragmin D. Real-time PCR and ATPase assays were performed to explore the mechanisms of reversion.Results: Swietephragmin D inhibited P-glycoprotein-induced efflux in a dose and time dependent manner. This compound inhibited P-glycoprotein more effectively than verapamil. The IC50values of the multidrug resistant cells were reduces by swietephragmin D significantly. The transcription levels of ABCB1 (encoded P-glycoprotein) were not affected by swietephragmin D. However, the ATPase activity of P-glycoprotein was stimulated by swietephragmin D.Conclusion: Swietephragmin D was a substrate of P-glycoprotein and inhibited P-gp mediated efflux. It did not interfere with expression of ABCB1. Thus swietephragmin D reversed multidrug resistance as a competitive inhibitor of P-glycoprotein.