黄腐酚查尔酮可作为耐药性人结肠癌致癌作用的强效抑制剂，这些作用是通过G2/M期细胞周期阻滞、凋亡途径激活、半胱天冬酶激活以及靶向Ras/MEK/ERK途径介导的。

Xanthohumol chalcone acts as a powerful inhibitor of carcinogenesis in drug-resistant human colon carcinoma and these effects are mediated via G2/M phase cell cycle arrest, activation of apoptotic pathways, caspase activation and targeting Ras /MEK/ERK pathway.

作者信息

Liu Xiaokang, An Li Juan, Li Yu, Wang Yanwei, Zhao Lei, Lv Xi, Guo Jinyi, Song Ai Lin

机构信息

Fifth Department of General Surgery, the Second Hospital of Lanzhou University, No.82 Cuiyingmen, Chennguan District, Lanzhou, 730030, Gan Su province, China.

出版信息

J BUON. 2019 Nov-Dec;24(6):2442-2447.

PMID:31983118

Abstract

PURPOSE

Xanthohumol is a prenylated flavonoid of plant origin and has been reported to exhibit a spectrum of pharmacological properties including anticancer effects. However, the anticancer properties of Xanthohumol have not been thoroughly evaluated against drug-resistant colon cancer cells. This study was undertaken to evaluate the anticancer effects of Xanthohumol against the human colon cancer cell line HT-29 and normal CDD-18Co cell line.

METHODS

HT-29 cell viability was evaluated by cell counting kit-8 (CCK8) assay. Apoptotic effects were examined by fluorescence microscopy using DAPI staining and flow cytometry using annexin V/propidium iodide (PI) staining. Effects on cell cycle were studied by flow cytometry while western blot analysis was done to study effects on protein expressions.

RESULTS

The results showed that Xanthohumol causes a dramatic decrease in the HT-29 cell viability with an IC50 of 10 µM. However, an IC50 >100 µM for Xanthohumol against the normal CDD-18Co cells suggested cancer cell specific activity. DAPI staining revealed nuclear fragmentation, suggesting xanthohumol induces apoptosis in HT-29 cells. Xanthohumol also caused activation of caspase-3 and 9 and increased the Bax/Bcl-2 ratio. Cell cycle analysis showed that this molecule caused arrest of the HT-29 cells at the G2/M phase of the cell cycle. The induction of G2/M cell cycle was also accompanied with depletion of the expression of cyclin B1. The effects of Xanthohumol were also investigated on the Ras/MEK/ERK signalling pathway which revealed that Xanthohumol also blocks the MEK/ERK signalling pathway in colon cancer cells in a concentration-dependent manner.

CONCLUSIONS

Xanthohumol may prove an efficient lead molecule for the development of more potent anticancer agents through semi-synthetic approaches.

摘要

目的

黄腐酚是一种植物源的异戊烯基黄酮，据报道具有一系列药理特性，包括抗癌作用。然而，黄腐酚对耐药结肠癌细胞的抗癌特性尚未得到充分评估。本研究旨在评估黄腐酚对人结肠癌细胞系HT-29和正常CDD-18Co细胞系的抗癌作用。

方法

采用细胞计数试剂盒-8（CCK8）法评估HT-29细胞活力。通过DAPI染色的荧光显微镜和膜联蛋白V/碘化丙啶（PI）染色的流式细胞术检测凋亡效应。通过流式细胞术研究对细胞周期的影响，同时进行蛋白质印迹分析以研究对蛋白质表达的影响。

结果

结果表明，黄腐酚可使HT-29细胞活力显著降低，IC50为10 μM。然而，黄腐酚对正常CDD-18Co细胞的IC50>100 μM，提示其具有癌细胞特异性活性。DAPI染色显示核碎裂，提示黄腐酚诱导HT-29细胞凋亡。黄腐酚还导致半胱天冬酶-3和9的激活，并增加Bax/Bcl-2比值。细胞周期分析表明，该分子使HT-29细胞停滞在细胞周期的G2/M期。G2/M细胞周期的诱导还伴随着细胞周期蛋白B1表达的减少。还研究了黄腐酚对Ras/MEK/ERK信号通路的影响，结果表明黄腐酚还以浓度依赖的方式阻断结肠癌细胞中的MEK/ERK信号通路。