雷尼霉素M的对苯二酚5-肉桂酰酯类似物对非小细胞肺癌细胞的凋亡诱导作用

Apoptosis-inducing Effect of Hydroquinone 5--Cinnamoyl Ester Analog of Renieramycin M on Non-small Cell Lung Cancer Cells.

作者信息

Maiuthed Arnatchai, Pinkhien Tatchakorn, Chamni Supakarn, Suwanborirux Khanit, Saito Naoki, Petpiroon Nareerat, Chanvorachote Pithi

机构信息

Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.

Cell-Based Drug and Health Product Development Research Unit, Chulalongkorn University, Bangkok, Thailand.

出版信息

Anticancer Res. 2017 Nov;37(11):6259-6267. doi: 10.21873/anticanres.12077.

DOI:10.21873/anticanres.12077

PMID:29061809

Abstract

BACKGROUND

A newly-synthesized derivative of renieramycin M (RM), an anticancer lead compound isolated from the blue sponge Xestospongia sp., hydroquinone 5-O-cinnamoyl ester (CIN-RM), was investigated here for its activity against non-small cell lung cancer cells.

MATERIALS AND METHODS

Cytotoxicity effects of CIN-RM and RM on H292 lung cancer cells were determined by the MTT assay. We also investigated the mechanism of CIN-RM-mediated apoptosis and mechanism of action of this compound by western blotting.

RESULTS

CIN-RM showed more potent cytotoxicity than its parental compound (RM) against H292 lung cancer cells. At concentrations of 15-60 μM, CIN-RM significantly induced apoptosis by increasing expression of apoptosis-inducing factor (AIF) and activation of caspase-3 and -9. For up-stream mechanism, CIN-RM mediated apoptosis through a p53-dependent mechanism, that consequently down-regulated anti-apoptotic B-cell lymphoma 2 (BCL2), while increasing the level of pro-apoptotic BCL2-associated X (BAX). In addition, phosphorylation of pro-survival protein AKT was found to be dramatically reduced.

CONCLUSION

This study revealed the potential of CIN-RM for apoptosis induction and in the development of a novel anticancer agent.

摘要

背景

从蓝色海绵Xestospongia sp.中分离出的抗癌先导化合物雷尼霉素M（RM）的一种新合成衍生物对苯二酚5 - O - 肉桂酸酯（CIN - RM），在此研究其对非小细胞肺癌细胞的活性。

材料与方法

通过MTT法测定CIN - RM和RM对H292肺癌细胞的细胞毒性作用。我们还通过蛋白质印迹法研究了CIN - RM介导的细胞凋亡机制和该化合物的作用机制。

结果

CIN - RM对H292肺癌细胞显示出比其母体化合物（RM）更强的细胞毒性。在15 - 60 μM浓度下，CIN - RM通过增加凋亡诱导因子（AIF）的表达以及激活半胱天冬酶 - 3和 - 9显著诱导细胞凋亡。对于上游机制，CIN - RM通过p53依赖性机制介导细胞凋亡，从而下调抗凋亡的B细胞淋巴瘤2（BCL2），同时增加促凋亡的BCL2相关X蛋白（BAX）的水平。此外，发现促生存蛋白AKT的磷酸化显著降低。