文章基本信息

标题：Reversal of P-Glycoprotein Mediated Multidrug Resistance in K562 Cell Line by a Novel Synthetic Calmodulin Inhibitor, E6
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作者：Hao-Jie Zhu ; Jun-Sheng Wang ; Qing-Long Guo 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2005
卷号：28
期号：10
页码：1974-1978
DOI：10.1248/bpb.28.1974
出版社：The Pharmaceutical Society of Japan
摘要：The overexpression of P-glycoprotein (P-gp) is associated with multidrug resistance (MDR) of tumor cells to a number of chemotherapeutic drugs. P-gp inhibitors have been shown to effectively reverse P-gp-mediated MDR in both in vitro and in vivo . Our previous studies demonstrated that E6, a novel synthetic calmodulin inhibitor, exhibited potent inhibitory effect on P-gp in rat brain microvessel endothelial cells (RBMECs). In the present study, the effect of E6 on MDR in a K562 MDR cell line (K562/DOX) highly expressing P-gp was studied and compared with that of a conventional P-gp inhibitor, verapamil (VER). E6 at concentrations of 1, 3, 10, 30 μ M reduced the IC₅₀ value of doxorubicin in K562/DOX cells from 79.19 μ M to 35.18, 21.86, 6.31 and 1.97 μ M , respectively. However, the IC₅₀ value of doxorubicin in K562 sensitive subline was not significantly changed by E6. Using a DNA content analysis and an annexin V binding assay, the effects of E6 on doxorubicin-induced apoptosis were also examined. The results indicated that E6 effectively reversed the resistance to doxorubicin-induced apoptosis in K562/DOX cells. In addition, co-treatment of E6 and doxorubicin resulted in a remarkably G2/M blocking effect in K562/DOX cells. Furthermore, the treatment of K562/DOX cells with 10 μ M E6 led to increased intracellular accumulation and decreased efflux of doxorubicin. Overall, the pharmacological effects of E6 on P-gp-mediated MDR is much stronger than that of positive control drug VER. These results suggested that E6 is a novel and potent MDR reversal agent and may be a potential adjunctive agent for tumor chemotherapy.
关键词：E6;doxorubicin;P-glycoprotein;multidrug resistance