Kim S H, Yeo G S, Lim Y S, Kang C D, Kim C M, Chung B S
Department of Biochemistry, College of Medicine, Pusan National University, Korea.
Exp Mol Med. 1998 Jun 30;30(2):87-92. doi: 10.1038/emm.1998.13.
MDR1 promoter has been shown to contain heat shock elements (HSE), and it has been reported that FM3A/M and P388/M MDR cells show a constitutively activated heat shock factor (HSF), suggesting that HSF might be an important target for reversing the multidrug resistance. Therefore, it was examined whether quercetin, which has been shown to interfere with the formation of the complex between HSE and HSF, and to downregulate the level of HSF1, can sensitize MDR cells against anticancer drugs by inhibition of HSF DNA-binding activity. In this study, quercetin appeared to inhibit the constitutive HSF DNA-binding activity and the sodium arsenite-induced HSF DNA-binding activity in the MDR cells. The basal and sodium arsenite-induced MDRCAT activities were remarkably suppressed by the treatment of quercetin. These results were well consistent with the finding that the treatment of quercetin decreased the expression level of P-gp, MDR1 gene product, in dose-dependent manner, and markedly increased the sensitivity of MDR cells to vincristine or vinblastine. These results suggest that quercetin can decrease the expression of P-gp via inhibition of HSF DNA-binding activity, and might be useful as a chemosensitizer in MDR cells.
多药耐药基因1（MDR1）启动子已被证明含有热休克元件（HSE），并且有报道称FM3A/M和P388/M多药耐药细胞显示出持续激活的热休克因子（HSF），这表明热休克因子可能是逆转多药耐药的一个重要靶点。因此，研究了槲皮素是否能通过抑制热休克因子与DNA的结合活性，使多药耐药细胞对抗癌药物敏感。槲皮素已被证明可干扰热休克元件与热休克因子之间复合物的形成，并下调热休克因子1（HSF1）的水平。在本研究中，槲皮素似乎能抑制多药耐药细胞中持续的热休克因子与DNA的结合活性以及亚砷酸钠诱导的热休克因子与DNA的结合活性。槲皮素处理可显著抑制基础及亚砷酸钠诱导的MDRCAT活性。这些结果与以下发现高度一致：槲皮素处理以剂量依赖方式降低了多药耐药基因1产物P-糖蛋白（P-gp）的表达水平，并显著增加了多药耐药细胞对长春新碱或长春花碱的敏感性。这些结果表明，槲皮素可通过抑制热休克因子与DNA的结合活性来降低P-糖蛋白的表达，并且可能作为多药耐药细胞中的化学增敏剂。
