天然产物EM-E-11-4逆转人口腔上皮癌细胞KBV200多药耐药作用及其机制

doi:10.19803/j.1672-8629.20220534

中国药物警戒 ›› 2023, Vol. 20 ›› Issue (4): 403-408.
DOI: 10.19803/j.1672-8629.20220534

天然产物EM-E-11-4逆转人口腔上皮癌细胞KBV200多药耐药作用及其机制

黄巍¹, 吴瑞卿¹, 孙华², 石建功², 刘潜^1,*

¹首都医科大学附属北京天坛医院,北京 100070;
²中国医学科学院药物研究所,北京 100050

收稿日期:2022-09-08 出版日期:2023-04-15 发布日期:2023-04-20
通讯作者: ^*刘潜,女,博士,副教授·硕导,肿瘤药理学。E-mail：liuqian1313@163.com
作者简介:黄巍,女,硕士,副主任医师,口腔内科。
基金资助:
国家自然科学基金资助项目（31800651、81502154）

Reversal of multidrug resistance in human oral epithelial cancer cells KBV200 by a natural product

HUANG Wei¹, WU Ruiqing¹, SUN Hua², SHI Jiangong², LIU Qian^1,*

¹Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing 100070, China;
²Institue of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China

Received:2022-09-08 Online:2023-04-15 Published:2023-04-20

摘要/Abstract

摘要： 目的考察无毒浓度千金烷二帖化合物EM-E-11-4对P-糖蛋白（P-glycoprotein,P-gp）介导人口腔上皮癌多药耐药（multi-drug resistance,MDR）的逆转作用并检测其对P-gp功能的影响。方法 MTT比色法测定EM-E-11-4对人口腔上皮癌KB及其具有多药耐药株表型的KBV200 细胞的细胞毒活性,采用维拉帕米为参比药,非细胞毒剂量EM-E-11-4（2.5、5、10 µmol·L-1）与3种常用抗癌药合用考察其逆转肿瘤多药耐药的作用,并计算逆转倍数。EM-E-11-4对P-gp的转运功能采用阿霉素蓄积实验检测。EM-E-11-4对基础与维拉帕米诱导的P-gp ATPase活性采用P-gp-GloTM试剂盒检测。结果 EM-E-11-4能够有效逆转P-gp介导的KBV200的多药耐药,并具有良好的剂量依赖关系。10 µmol·L-1 EM-E-11-4能够逆转KBV200细胞对紫杉醇、长春新碱和阿霉素3种抗癌药物的耐药作用,逆转倍数分别为33.8、36.4、20.1。无细胞毒作用的EM-E-11-4对P-gp的转运功能有显著抑制作用,并且能够增加阿霉素在肿瘤细胞内的蓄积,具有良好的浓度依赖性。同时,EM-E-11-4能明显抑制维拉帕米刺激的重组P-gp的ATPase活性。结论 EM-E-11-4能逆转P-gp介导的肿瘤多药耐药,其作用机制与抑制P-gp的转运功能有关,为其临床治疗口腔上皮癌肿瘤多药耐药提供了理论依据。

关键词: 千金烷二帖, 口腔上皮癌, 多药耐药, P-糖蛋白, 紫杉醇, 长春新碱, 阿霉素

Abstract: Objective To investigate the ability of a natural product EM-E-11-4 at non-cytotoxic concentrations to reverse P-gp-mediated multidrug resistance (MDR) in human oral epithelial cancer cells KBV200 and to reveal the mechanism of action. Methods The effect of EM-E-11-4 on the growth of KB cells and the corresponding resistant cells KBv200 was determined by MTT assay. Using VRP as positive control, the ability of non-cytotoxic concentrations of EM-E-11-4 (2.5, 5, 10 µmol·L-1) with/without such chemotherapeutic agents as paclitaxel vincristine and adriamycin to reverse MDR was evaluated, while the reversal folds (RF) of EM-E-11-4 and VRP were calculated and compared. The effect of EM-E-11-4 and VRP on the accumulation and efflux function of P-gp was studied. Furthermore, the effect of EM-E-11-4 on the ATPase activity of P-gp was measured by Pgp-GloTM kit. Results 10 µmol·L-1 of EM-E-11-4 effectively reversed the MDR-phenotype of KBv200 cells to paclitaxel, vincristine and adriamycin. The RF was 33.8、36.4 and 20.1, respectively. In addition, the P-gp functional study suggested that EM-E-11-4 elevated the intracellular accumulation of adriamycin in a dose-dependent manner. EM-E-11-4 suppressed VRP-stimulated ATPase activity of P-gp in a dose-dependent manner. Conclusion EM-E-11-4 can be a potential agent that can overcome P-gp-mediated MDR by suppressing the transport function of P-gp.

Key words: EM-E-11-4, oral squamous epithelium tumor, multi-drug resistance, P-glycoprotein, paclitaxel, vincristine, adriamycin

中图分类号:

黄巍, 吴瑞卿, 孙华, 石建功, 刘潜. 天然产物EM-E-11-4逆转人口腔上皮癌细胞KBV200多药耐药作用及其机制[J]. 中国药物警戒, 2023, 20(4): 403-408.

HUANG Wei, WU Ruiqing, SUN Hua, SHI Jiangong, LIU Qian. Reversal of multidrug resistance in human oral epithelial cancer cells KBV200 by a natural product[J]. Chinese Journal of Pharmacovigilance, 2023, 20(4): 403-408.

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天然产物EM-E-11-4逆转人口腔上皮癌细胞KBV200多药耐药作用及其机制

Reversal of multidrug resistance in human oral epithelial cancer cells KBV200 by a natural product

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