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01-04-2020 | Gastric Cancer | PRECLINICAL STUDIES

Cardamonin, a natural chalcone, reduces 5-fluorouracil resistance of gastric cancer cells through targeting Wnt/β-catenin signal pathway

Authors: Gaochao Hou, Xiang Yuan, Yi Li, Gaoyu Hou, Xianli Liu

Published in: Investigational New Drugs | Issue 2/2020

Summary

Objectives Cardamonin (CD), an active chalconoid, has been extensively studied in a wide variety of human tumors. However, the effects and underlying mechanism of cardamonin on 5-fluorouracil (5-FU)-resistant gastric cancer (GC) remain largely unclear. This study aimed to investigate the antitumor effects of cardamonin on 5-FU-resistant GC cells and explore the molecular mechanisms underlying its therapeutic potential. Methods The antitumor activities of cardamonin, 5-FU and their combination against BGC-823 and BGC-823/5-FU cells were determined using cytotoxicity assay, flow cytometry-based cell cycle analysis and Annexin V apoptosis assay. The effect of cardamonin on P-glycoprotein activity was assessed by Rh123 uptake assay. Real-time PCR, Western blotting and Co-immunoprecipitation analysis were carried out to assess the inhibition of Wnt/β-catenin signaling pathway. A xenograft mouse model was established using BALB/c nude mice to examine the combinatorial effects of cardamonin and 5-FU on tumor growth. Results Our data provided the first demonstration that cardamonin significantly enhanced the chemosensitivity of 5-FU in GC cells via suppression of Wnt/β-catenin signaling pathway. Additionally, the combination of cardamonin and 5-FU might result in the apoptosis and cell cycle arrest of BGC-823/5-FU cells, accompanied by the downregulated expression levels of P-glycoprotein, β-catenin and TCF4. More importantly, our results demonstrated that cardamonin specifically disrupted the formation of β-catenin/TCF4 complex, leading to TCF4-mediated transcriptional activation in 5-FU-resistant GC cells. Besides, through a xenograft mouse model, co-administration of cardamonin and 5-FU significantly retarded tumor growth in vivo, thus, confirming our in vitro findings. Conclusions Overall, this study revealed that cotreatment of cardamonin and 5-FU could strongly potentiate the antitumor activity of 5-FU, and put forth cardamonin as a rational therapeutic strategy for drug-resistant GC treatment.

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Title: Cardamonin, a natural chalcone, reduces 5-fluorouracil resistance of gastric cancer cells through targeting Wnt/β-catenin signal pathway
Authors: Gaochao Hou
Xiang Yuan
Yi Li
Gaoyu Hou
Xianli Liu
Publication date: 01-04-2020
Publisher: Springer US
Keywords: Gastric Cancer
Gastric Cancer
Published in: Investigational New Drugs / Issue 2/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-019-00781-9

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