Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
Eur J Pharmacol. 2010 Jan 25;626(2-3):139-45. doi: 10.1016/j.ejphar.2009.09.040. Epub 2009 Sep 24.
P-glycoprotein (P-gp), a membrane transporter encoded by the MDR1 gene in human cells, mediates drug efflux from cells and plays a major role in causing multidrug resistance; which is one of the most accepted mechanisms for failure of chemotherapy in cancer treatment. In this study, we investigated the effects of nine naturally occurring compounds isolated from Citrus jambhiri Lush and Citrus pyriformis Hassk (Rutaceae) for their potential to modulate the activity of P-gp in the multidrug-resistant human leukaemia cell line CEM/ADR5000. Limonin, deacetylnomilin, hesperidin, neohesperidin, stigmasterol and ss-sitosterol-O-glucoside inhibited the efflux of the P-gp substrate rhodamine 123 in a concentration-dependent manner. Some of these compounds were more active than verapamil, which was used as a positive control. Treatment of drug-resistant Caco-2 cells with the most active C. jambhiri and C. pyriformis compounds increased their sensitivity to doxorubicin and completely reversed doxorubicin resistance, which agrees with a decreased P-gp activity. Limonin was the most potent P-glycoprotein inhibitor - when it was applied at a non-toxic concentration of 20 microM, it significantly enhanced doxorubicin cytotoxicity 2.98-fold (P<0.001) and 2.2-fold (P<0.001) in Caco2 and CEM/ADR5000 cells, respectively. These isolated Citrus compounds could be considered as good candidates for the development of novel P-gp/MDR1 reversal agents which may enhance the accumulation and efficacy of chemotherapy agents.
P-糖蛋白（P-gp）是人类细胞中 MDR1 基因编码的一种膜转运蛋白，介导药物从细胞内流出，在导致多药耐药中起主要作用；这是癌症治疗中化疗失败的最被接受的机制之一。在这项研究中，我们研究了从枳属（芸香科）Citrus jambhiri Lush 和 Citrus pyriformis Hassk 中分离的九种天然化合物对多药耐药人白血病细胞系 CEM/ADR5000 中 P-gp 活性的潜在调节作用。柠檬苦素、去乙酰诺米林、柚皮苷、新橙皮苷、豆甾醇和 ss-谷甾醇-O-葡萄糖苷以浓度依赖的方式抑制 P-糖蛋白底物罗丹明 123 的外排。其中一些化合物比用作阳性对照的维拉帕米更有效。用最有效的枳属和枳属化合物处理耐药 Caco-2 细胞，增加了它们对阿霉素的敏感性，并完全逆转了阿霉素耐药性，这与 P-gp 活性降低一致。柠檬苦素是最有效的 P-糖蛋白抑制剂 - 当它以非毒性浓度 20 μM 应用时，它分别显着增强了 Caco2 和 CEM/ADR5000 细胞中阿霉素的细胞毒性 2.98 倍（P<0.001）和 2.2 倍（P<0.001）。这些分离的柑橘属化合物可被认为是开发新型 P-gp/MDR1 逆转剂的良好候选物，它们可能增强化疗药物的积累和疗效。
