Xu Hong-Bin, Li Ling, Liu Guo-Qing
Department of Pharmacy, Tenth People's Hospital, Tongji University, Shanghai, China.
Pharmazie. 2009 Oct;64(10):660-5.
Multidrug resistance (MDR) has been a major problem in cancer chemotherapy. The development of P-glycoprotein inhibitors could be effective to reverse multidrug resistance. The aim of this study was to observe the effects of guggulsterone, the active component of gugulipid, on multidrug resistance in doxorubicin-resistant K562 cells (K562/DOX) and the parental K562 cells. Its cytotoxicity and reversal effects on multidrug resistance were assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Apoptosis percentage of cells was obtained from Annexin V/fluorescein isothiocyanate (FITC) and propridium iodide (PI) double staining. The effects of guggulsterone on P-glycoprotein activity were evaluated by measuring rhodamine 123 (Rh123)-associated mean fluorescence intensity and P-glycoprotein expression on the basis of the flow cytometric technology, respectively. The results showed that guggulsterone up to 100 microM had little cytotoxicity against K562/DOX cells. When combined with doxorubicin, it significantly promoted the sensitivity of K562/DOX cells toward doxorubicin through increasing intracellular accumulation of doxorubicin in a dose-dependent manner. Further study demonstrated that the inhibitory effect of guggulsterone on P-glycoprotein activity was the major cause of increased stagnation of doxorubicin inside K562/DOX cells, indicating that guggulsterone may effectively reverse multidrug resistance in K562/DOX cells via inhibiting expression and drug-transport function of P-glycoprotein.
多药耐药性（MDR）一直是癌症化疗中的一个主要问题。P-糖蛋白抑制剂的开发可能有效地逆转多药耐药性。本研究的目的是观察古古甾酮（一种古古脂的活性成分）对阿霉素耐药的K562细胞（K562/DOX）和亲代K562细胞多药耐药性的影响。通过MTT（3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐）试验评估其细胞毒性和对多药耐药性的逆转作用。细胞凋亡率通过膜联蛋白V/异硫氰酸荧光素（FITC）和碘化丙啶（PI）双染色获得。分别基于流式细胞术通过测量罗丹明123（Rh123）相关的平均荧光强度和P-糖蛋白表达来评估古古甾酮对P-糖蛋白活性的影响。结果表明，高达100微摩尔的古古甾酮对K562/DOX细胞几乎没有细胞毒性。当与阿霉素联合使用时，它通过以剂量依赖的方式增加阿霉素在细胞内的积累，显著提高了K562/DOX细胞对阿霉素的敏感性。进一步的研究表明，古古甾酮对P-糖蛋白活性的抑制作用是阿霉素在K562/DOX细胞内滞留增加的主要原因，这表明古古甾酮可能通过抑制P-糖蛋白的表达和药物转运功能有效地逆转K562/DOX细胞中的多药耐药性。
