4.6 Article

The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKK? and overcomes gefitinib resistance in non-small cell lung cancer

期刊

CANCER BIOLOGY & MEDICINE
卷 19, 期 8, 页码 1172-1192

出版社

CHINA ANTI-CANCER ASSOC
DOI: 10.20892/j.issn.2095-3941.2021.0130

关键词

HDAC inhibitor; c-Met; IKK?; NSCLC; gefitinib

资金

  1. National Natural Science Foundation of China [81773763, 81521005]

向作者/读者索取更多资源

This study found that GCJ-490A effectively inhibited the proliferation of NSCLC cells and induced apoptosis both in vitro and in vivo. Furthermore, GCJ-490A increased histone acetylation at the IKK?? promoter by inhibiting HDAC1 and HDAC6, resulting in the downregulation of c-Met. This downregulation was essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib. These findings provide a potential strategy for NSCLC treatment by using HDAC inhibitors in combination with EGFR inhibitors.
inhibitory activity against HDAC1, HDAC3, and HDAC6. Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue, we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer (NSCLC) in vitro and in vivo in this study. Methods: The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation, apoptosis, and colony formation assays. NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo. Western blot assays, luciferase reporter assays, chromatin immunoprecipitation assays, quantitative real time-PCR, immunohistochemistry, and transcription factor activity assays were used to elucidate possible mechanisms. Results: GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo. Interestingly, inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKK?? promoter and enhanced IKK?? transcription, thus decreasing c-Met. Moreover, this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib. Conclusions: These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据