Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder
Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder
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DOI：
10.1016/j.bcp.2004.07.009
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发表时间：
2004-11-15
影响因子：
5.8
通讯作者：
Limtrakul, P
中科院分区：
文献类型：
--
作者：
Chearwae, W;Anuchapreeda, S;Limtrakul, P
p -糖蛋白（Pgp, ABCB1）是atp依赖的药物外排泵，与癌细胞多药耐药（MDR）的发展有关。previous previous [Biochem Pharmacol 2002；[64:573-82]，我们报道了姜黄素混合物可以调节Pgp的功能和表达。本研究主要研究从姜黄素混合物中纯化的三种主要姜黄素-姜黄素I， II和III -对多药耐药人宫颈癌细胞系（KB-V1） Pgp功能的调节作用。KB-V1和KB-3-1（亲本药敏细胞系）的姜黄素细胞毒性IC50值相似，提示这些姜黄素可能不是Pgp的底物。用无毒剂量的姜黄素处理细胞仅在表达Pgp的耐药细胞系中增加了对长春花碱的敏感性，KB-V1和姜黄素I分别比姜黄素II和III更有效地保留了KB-V1细胞中的药物。每种姜黄素对罗丹明123、钙黄素- am和体脂- fl -长春碱积累的影响证实了这些发现。姜黄素I、II和III以剂量依赖的方式增加荧光底物的积累，在15 muM时，姜黄素I的效果最好。姜黄素对维拉帕米刺激的atp酶活性呈浓度依赖性的抑制作用和[I-125]-碘arylazidoprazosin对Pgp的光亲和性标记提供了额外的支持；姜黄素I是最有效的调节剂。综上所述，这些结果表明姜黄素I是姜黄素类中最有效的MDR调节剂，可以与常规化疗药物联合使用来逆转癌细胞的MDR。(C) 2004爱思唯尔公司版权所有。
P-glycoprotein (Pgp, ABCB1) is an ATP-dependent drug efflux pump linked to development of multidrug resistance (MDR) in cancer cells. Previously [Biochem Pharmacol 2002;64:573-82], we reported that a curcumin mixture could modulate both function and expression of Pgp. This study focuses on the effect of three major curcuminoids - curcumin I, II and III purified from a curcumin mixture - on modulation of Pgp function in a multidrug resistant human cervical carcinoma cell line (KB-V1). The similar IC50 values for cytotoxicity of curcuminoids of KB-V1, and KB-3-1 (parental drug sensitive cell line) suggest that these curcuminoids may not be substrates for Pgp. Treating the cells with non-toxic doses of curcuminoids increased their sensitivity to vinblastine only in the Pgp expressing drug resistant cell line, KB-V1, and curcumin I retained the drug in KB-V1 cells more effectively than curcumin II and III, respectively. Effects of each curcuminoid on rhodamine123, calcein-AM, and bodipy-FL-vinblastine accumulation confirmed these findings. Curcumin I, II and III increased the accumulation of fluorescent substrates in a dose-dependent manner, and at 15 muM, curcumin I was the most effective. The inhibitory effect in a concentration-dependent manner of curcuminoids on verapamil-stimulated ATPase activity and photoaffinity labeling of Pgp with the [I-125]-iodoarylazidoprazosin offered additional support; curcumin I was the most potent modulator. Taken together, these results indicate that curcumin I is the most effective MDR modulator among curcuminoids, and may be used in combination with conventional chemotherapeutic drugs to reverse MDR in cancer cells. (C) 2004 Elsevier Inc. All rights reserved.