Dibenzocyclooctadiene lingnans: a class of novel inhibitors of P-glycoprotein
Dibenzocyclooctadiene lingnans: a class of novel inhibitors of P-glycoprotein
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DOI：
10.1007/s00280-005-0133-1
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发表时间：
2006-07-01
影响因子：
3
通讯作者：
Hu, X
中科院分区：
文献类型：
--
作者：
Pan, QR;Lu, QH;Hu, X
目的：确定五种二苯并环辛二烯岭南化合物（一类来自五味子的天然化合物）是否具有逆转 P-糖蛋白（P-gp）介导的多药耐药性（MDR）的活性。方法：通过 FACscan 测定，在存在或不存在一种二苯并环辛二烯岭南的情况下，测定四种 MDR 细胞系（K562/Adr、MCF-7/Adr、KBv200 和 Bcap37/Adr）对柔红霉素、长春新碱和紫杉醇的 IC(50)。通过FACscan测定，在存在或不存在一种二苯并环辛二烯岭南的情况下将细胞与柔红霉素(2μg/ml)一起温育，测定四种MDR细胞系中柔红霉素的细胞内积累。通过抑制 P-gp 的 H-3-叠氮平光亲和标记来测定五种二苯并环辛二烯岭南化合物与 P-gp 的相互作用。结果：在五种岭南药中，五味子A和B以及五味子A在四种MDR细胞系中表现出很强且相当的逆转耐药性和细胞内药物蓄积的活性，而五味子A和B表现出非常有限的活性。五味子A和B的活性差可能是环辛二烯环上的羟基造成的，因为当羟基被酯化形成苯甲酸酯时，分子的活性又恢复了。进一步的研究表明这些化合物与 P-gp 发生物理相互作用。结论：五味子甲素、五味子乙素和五味子乙素A是有效的P-gp抑制剂，具有潜在的临床应用前景。
Purpose: To determine if five dibenzocyclooctadiene lingnans, a class of naturally occurring compounds from Schisandra chinensis (Turcz.) Baill, have the activities to reverse P-glycoprotein (P-gp) mediated multidrug resistance (MDR). Methods: The IC(50)s of four MDR cell lines (K562/Adr, MCF-7/Adr, KBv200, and Bcap37/Adr) toward daunorubicin, vincristine, and paclitaxel in the presence or absence of one of the dibenzocyclooctadiene lingnans were determined by a FACscan assay. The intracellular daunorubicin accumulation in the four MDR cell lines was determined by incubation of cells with daunorubicin (2 mu g/ml) in the presence or absence of one of the dibenzocyclooctadiene lingnans by a FACscan assay. The interaction of the five dibenzocyclooctadiene lingnans with P-gp was assayed by their inhibition of H-3-azidopine photoaffinity labeling of P-gp. Results: Among the five lingnans, while schisandrin A and B, and schisantherin A demonstrated strong and comparable activities to reverse the drug resistance and the intracellular drug accumulation in four MDR cell lines, schisandrol A and B showed very limited activities. The poor activities of schisandrol A and B are possibly caused by the hydroxyl groups on the cyclooctadiene ring, because the activities of the molecules resumed when the hydroxyl group was esterified to form a benzoate. Further studies demonstrated that these compounds physically interacted with P-gp. Conclusion: Schisandrin A and B, and schisantherin A are potent P-gp inhibitor and is of potential for future clinical application.