Shi Yan-Qiu, Qu Xian-Jun, Liao Yong-Xiang, Xie Chun-Feng, Cheng Yan-Na, Li Song, Lou Hong-Xiang
School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
Eur J Pharmacol. 2008 Apr 14;584(1):66-71. doi: 10.1016/j.ejphar.2008.01.039. Epub 2008 Feb 5.
Plagiochin E is a new macrocyclic bisbibenzyl compound isolated from Marchantia polymorpha. In the previous studies, we reported that when combined with fluconazole, plagiochin E had synergetic effects against the resistant strain of Candida albicans. Herein, we examined the reversal effect of plagiochin E on multidrug resistance in adriamycin-induced resistant K562/A02 cells 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-diphenyl-tetrazolium bromide) assay. Apoptosis percentage of cells was obtained from Annexin V/fluorescein isothiocyanate (FITC) and propridium iodide (PI) double-staining. The effects of plagiochin E 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 plagiochin E ranging from 2 to 12 mug/ml had little cytotoxicity against K562/A02 cells. When combined with adriamycin, it significantly promoted the sensitivity of K562/A02 cells toward adriamycin through increasing intracellular accumulation of adriamycin in a dose-dependent manner. Further study demonstrated that the inhibitory effect of plagiochin E on P-glycoprotein activity was the major cause of increased stagnation of adriamycin inside K562/A02 cells, indicating that plagiochin E, as a new class of mutidrug resistance inhibitor, may effectively reverse the multidrug resistance in K562/A02 cells via inhibiting expression and drug-transport function of P-glycoprotein.
斜生栅藻素E是从多形苔中分离出的一种新型大环双苄基化合物。在先前的研究中，我们报道斜生栅藻素E与氟康唑联合使用时，对白色念珠菌耐药菌株具有协同作用。在此，我们研究了斜生栅藻素E对阿霉素诱导的耐药K562/A02细胞和亲本K562细胞多药耐药性的逆转作用。通过MTT（3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四氮唑）法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-糖蛋白表达来评估斜生栅藻素E对P-糖蛋白活性的影响。结果表明，浓度为2至12μg/ml的斜生栅藻素E对K562/A02细胞几乎没有细胞毒性。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/A02细胞对阿霉素的敏感性。进一步研究表明，斜生栅藻素E对P-糖蛋白活性的抑制作用是阿霉素在K562/A02细胞内滞留增加的主要原因，这表明斜生栅藻素E作为一类新型的多药耐药抑制剂，可能通过抑制P-糖蛋白的表达和药物转运功能有效逆转K562/A02细胞的多药耐药性。
