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

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)27580-27595
Number of pages16
JournalOncotarget
Volume6
Issue number29
DOIs
Publication statusPublished - 2015

Fingerprint

Sirtuin 1
Chlorpromazine
Antipsychotic Agents
Colorectal Neoplasms
JNK Mitogen-Activated Protein Kinases
Apoptosis
Neoplasms
Drug Repositioning
Histone Deacetylases
Acetylation
Pharmaceutical Preparations
Down-Regulation

Keywords

  • Apoptosis
  • Chlorpromazine
  • Drug reposition
  • P53
  • SIRT1

ASJC Scopus subject areas

  • Oncology

Cite this

Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1. / Lee, Wen Ying; Lee, Wai Theng; Cheng, Chia Hsiung; Chen, Ku Chung; Chou, Chih Ming; Chung, Chu Hung; Sun, Min Siou; Cheng, Hung Wei; Ho, Meng Ni; Lin, Cheng Wei.

In: Oncotarget, Vol. 6, No. 29, 2015, p. 27580-27595.

Research output: Contribution to journalArticle

Lee, Wen Ying ; Lee, Wai Theng ; Cheng, Chia Hsiung ; Chen, Ku Chung ; Chou, Chih Ming ; Chung, Chu Hung ; Sun, Min Siou ; Cheng, Hung Wei ; Ho, Meng Ni ; Lin, Cheng Wei. / Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1. In: Oncotarget. 2015 ; Vol. 6, No. 29. pp. 27580-27595.
@article{8e031b249ad94e29ad77c80348da265a,
title = "Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1",
abstract = "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.",
keywords = "Apoptosis, Chlorpromazine, Drug reposition, P53, SIRT1",
author = "Lee, {Wen Ying} and Lee, {Wai Theng} and Cheng, {Chia Hsiung} and Chen, {Ku Chung} and Chou, {Chih Ming} and Chung, {Chu Hung} and Sun, {Min Siou} and Cheng, {Hung Wei} and Ho, {Meng Ni} and Lin, {Cheng Wei}",
year = "2015",
doi = "10.18632/oncotarget.4768",
language = "English",
volume = "6",
pages = "27580--27595",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "29",

}

TY - JOUR

T1 - Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1

AU - Lee, Wen Ying

AU - Lee, Wai Theng

AU - Cheng, Chia Hsiung

AU - Chen, Ku Chung

AU - Chou, Chih Ming

AU - Chung, Chu Hung

AU - Sun, Min Siou

AU - Cheng, Hung Wei

AU - Ho, Meng Ni

AU - Lin, Cheng Wei

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Chlorpromazine

KW - Drug reposition

KW - P53

KW - SIRT1

UR - http://www.scopus.com/inward/record.url?scp=84944463989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84944463989&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.4768

DO - 10.18632/oncotarget.4768

M3 - Article

VL - 6

SP - 27580

EP - 27595

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 29

ER -