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.
authors.affiliation: Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan.|Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wai-Theng
authors.initials: WT
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Hsiung
authors.initials: CH
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ku-Chung
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Chou
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Chu-Hung
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Min-Siou
authors.initials: MS
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Wei
authors.initials: HW
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Meng-Ni
authors.initials: MN
authors.lastname: Ho
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Medical Sciences, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D002746:Chlorpromazine / Q000737:chemistry / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D058492:Drug Repositioning; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D017354:Point Mutation; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014150:Antipsychotic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D048670:MAP Kinase Kinase 4; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D002746:Chlorpromazine
keywords: SIRT1; apoptosis; chlorpromazine; drug reposition; p53