10-苯并三唑青蒿素是一种新型 P-糖蛋白抑制剂，可抑制 P-糖蛋白的过度表达和功能。

10-Phenyltriazoyl Artemisinin is a Novel P-glycoprotein Inhibitor that Suppresses the Overexpression and Function of P-glycoprotein.

机构信息

Hallym Institute for Clinical Medicine, Hallym University Medical Center, Anyang, 14066, Korea.

Department of Pharmacy, Noakhali Science and Technology University, Sonapur, Noakhali 3814, Bangladesh.

出版信息

Curr Pharm Des. 2018;24(46):5590-5597. doi: 10.2174/1381612825666190222155700.

DOI:10.2174/1381612825666190222155700

PMID:30799787

Abstract

BACKGROUND

The effect of drugs on ATP-binding cassette transporters, especially permeabilityglycoprotein (P-gp), is an important consideration during new anti-cancer drug development.

OBJECTIVE

In this context, the effects of a newly synthesized artemisinin derivative, 10-(4-phenyl-1H-1,2,3- triazol)-artemisinin (5a), were evaluated on P-gp expression and function.

METHODS

Reverse transcript polymerase chain reaction and immunoblotting techniques were used to determine the effect of 5a on P-gp expression in LS174T cells. In addition, the ability of 5a to work as either a substrate or an inhibitor of P-gp was investigated through different methods.

RESULTS

The results revealed that 5a acts as a novel P-gp inhibitor that dually suppresses the overexpression and function of P-glycoprotein. Co-treatment of LS174T cell line, human colon adenocarcinoma cell line, with 5a and paclitaxel recovered the anticancer effect of paclitaxel by controlling the acquired drug resistance pathway. The overexpression of P-gp induced by rifampin and paclitaxel in a colorectal cell line was suppressed by 5a which could be a novel inhibitory substrate inhibiting the transport of paclitaxel by P-gp.

CONCLUSION

The results revealed that 5a can be classified as a type B P-gp inhibitor (with both substrate and inhibitor activities) with an additional function of suppressing P-gp overexpression. The results might be clinically useful in the development of anticancer drugs against cancers with multidrug resistance.

摘要

背景

药物对 ABC 转运蛋白的影响，尤其是对 P-糖蛋白（P-gp）的影响，是新抗癌药物开发过程中的一个重要考虑因素。

目的

在这种情况下，评估了一种新合成的青蒿素衍生物 10-（4-苯基-1H-1,2,3-三唑）-青蒿素（5a）对 P-gp 表达和功能的影响。

方法

采用逆转录聚合酶链反应和免疫印迹技术测定 5a 对 LS174T 细胞中 P-gp 表达的影响。此外，通过不同的方法研究了 5a 作为 P-gp 底物或抑制剂的能力。

结果

结果表明，5a 是一种新型的 P-gp 抑制剂，可双重抑制 P-糖蛋白的过度表达和功能。用 5a 和紫杉醇共同处理 LS174T 细胞系，人结肠腺癌细胞系，通过控制获得性耐药途径，恢复了紫杉醇的抗癌作用。5a 抑制了由利福平诱导的和紫杉醇诱导的在结直肠细胞系中的 P-gp 过表达，这可能是一种新型的抑制底物，可抑制 P-gp 对紫杉醇的转运。