Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1

Wen Ying Lee, Wai Theng Lee, Chia Hsiung Cheng, Ku Chung Chen, Chih Ming Chou, Chu Hung Chung, Min Siou Sun, Hung Wei Cheng, Meng Ni Ho, Cheng Wei Lin

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32 引文 斯高帕斯(Scopus)

摘要

Investigating existing drugs for repositioning can enable overcoming bottlenecks in the drug development process. Here, we investigated the effect and molecular mechanism of the antipsychotic drug chlorpromazine (CPZ) and identified its potential for treating colorectal cancer (CRC). Human CRC cell lines harboring different p53 statuses were used to investigate the inhibitory mechanism of CPZ. CPZ effectively inhibited tumor growth and induced apoptosis in CRC cells in a p53-dependent manner. Activation of c-jun N-terminal kinase (JNK) was crucial for CPZ-induced p53 expression and the subsequent induction of tumor apoptosis. Induction of p53 acetylation at lysine382 was involved in CPZ-mediated tumor apoptosis, and this induction was attenuated by sirtuin 1 (SIRT1), a class III histone deacetylase. By contrast, knocking down SIRT1 sensitized tumor cells to CPZ treatment. Moreover, CPZ induced the degradation of SIRT1 protein participating downstream of JNK, and JNK suppression abrogated CPZ-mediated SIRT1 downregulation. Clinical analysis revealed a significant association between high SIRT1 expression and poor outcome in CRC patients. These data suggest that SIRT1 is an attractive therapeutic target for CRC and that CPZ is a potential repositioned drug for treating CRC.
原文英語
頁(從 - 到)27580-27595
頁數16
期刊Oncotarget
6
發行號29
DOIs
出版狀態已發佈 - 2015

ASJC Scopus subject areas

  • 腫瘤科

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