Research Papers:

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 and Cheng-Wei Lin _

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Oncotarget. 2015; 6:27580-27595. https://doi.org/10.18632/oncotarget.4768

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Wen-Ying Lee1,2, Wai-Theng Lee3, Chia-Hsiung Cheng3,4, Ku-Chung Chen3,4, Chih-Ming Chou3,4, Chu-Hung Chung5, Min-Siou Sun5, Hung-Wei Cheng3, Meng-Ni Ho3, Cheng-Wei Lin3,4

1Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan

2Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

3Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

4Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

5Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan

Correspondence to:

Cheng-Wei Lin, e-mail: [email protected]

Keywords: chlorpromazine, drug reposition, p53, apoptosis, SIRT1

Received: May 04, 2015     Accepted: August 24, 2015     Published: September 05, 2015


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.

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