EFFECTS OF INDOLE ALKALOIDS ON MULTIDRUG RESISTANCE AND LABELING OF P-GLYCOPROTEIN BY A PHOTOAFFINITY ANALOG OF VINBLASTINE
EFFECTS OF INDOLE ALKALOIDS ON MULTIDRUG RESISTANCE AND LABELING OF P-GLYCOPROTEIN BY A PHOTOAFFINITY ANALOG OF VINBLASTINE
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DOI：
10.1016/s0006-291x(88)81321-4
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发表时间：
1988-06-30
影响因子：
3.1
通讯作者：
SAFA, AR
中科院分区：
文献类型：
--
作者：
BECK, WT;CIRTAIN, MC;SAFA, AR
多重耐药细胞的特点是药物积累和滞留减少，被认为是由高分子量糖蛋白p -糖蛋白（P-gp）介导的。维拉帕米等药物已被证明可以增加抗癌药物的细胞毒性，并增加这些细胞积累和保留的药物量。我们在这里表明，除了维拉帕米，利血平、氯喹、奎宁、奎纳克里、育亨宾、长春多林和长春花碱也增强了长春花碱（VLB）对多药耐药的人白血病细胞系CEM/VLB1K的细胞毒性，这是首次在这里描述。这些细胞将P-gp表达为双链，通过类似物VLB标记N（p-axido-[3-125I]水杨基）-N''- β进行光亲和。-aminoethylvindesine ([125 i] NASV)。利血平和维拉帕米（在较小程度上）都与[125I]NASV竞争P-gp结合。我们还发现，氯喹、奎宁、vindoline和catharanthine均能将VLB在CEM/VLB1K细胞中的细胞毒性提高10- 15倍，类似地抑制P-gp的NASV标记[125I]。然而，奎宁和育himine都没有抑制这种标记，catharanthine和vindoline产生的抑制作用最大或仅在P-gp双峰的下带。我们的研究结果表明，化合物调节MDR的能力与其竞争P-gp结合的能力之间存在复杂的关系。
Multidrug resistant cells are characterized by decreased drug accumulation and retention, thought to be mediated by a high molecular weight glycoprotein, P-glycoprotein (P-gp). Agents such as verapamil have been shown to increase anticancer drug cytotoxicity and increase the amount of drug accumulated and retained by such cells. We show here that in addition to verapamil, reserpine, chloroquine, quinine, quinacrine, yohimbine, vindoline, and catharanthine also enhanced the cytotoxicity of vinblastine (VLB) in a multidrug resistant, human leukemic cell line, CEM/VLB1K, described here for the first time. These cells express P-gp as a doublet that is photoaffinity labeled by the analog of VLB, N(p-axido-[3-125I]salicyl)-N''-.beta.-aminoethylvindesine ([125I]NASV). Both reserpine and, to a lesser extent, verapamil, compete with [125I]NASV for binding to P-gp. We also found that chloroquine, quinacrine, vindoline, and catharanthine, each of which enhanced VLB cytotoxicity in CEM/VLB1K cells by 10- to 15-fold, similarly inhibited [125I]NASV labeling of P-gp. However, neither quinine nor yohimbine inhibited this labeling, and the inhibition produced by catharanthine and vindoline was the greatest or exclusively on the lower band of the P-gp doublet. Our results suggest a complex relationship between the ability of a compound to modulate MDR and its ability to compete for binding to P-gp.