title: Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer.
abstract: BACKGROUND
  Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance.
  
  
  OBJECTIVE
  To screen drugs that target CSCs to improve the current treatment outcome and overcome drug resistance in patients with lung cancer.
  
  
  METHODS
  We used publicly available embryonic stem cell and CSC-associated gene signatures to query the Connectivity Map for potential drugs that can, at least in part, reverse the gene expression profile of CSCs. High scores were noted for several phenothiazine-like antipsychotic drugs, including trifluoperazine. We then treated lung CSCs with different EGFR mutation status with trifluoperazine to examine its anti-CSC properties. Lung CSCs resistant to epidermal growth factor receptor-tyrosine kinase inhibitor or cisplatin were treated with trifluoperazine plus gefitinib or trifluoperazine plus cisplatin. Animal models were used for in vivo validation of the anti-CSC effect and synergistic effect of trifluoperazine with gefitinib.
  
  
  RESULTS
  We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazine inhibited Wnt/β-catenin signaling in gefitinib-resistant lung cancer spheroids. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models.
  
  
  CONCLUSIONS
  Using in silico drug screening by Connectivity Map followed by empirical validations, we repurposed an existing phenothiazine-like antipsychotic drug, trifluoperazine, as a potential anti-CSC agent that could overcome epidermal growth factor receptor-tyrosine kinase inhibitor and chemotherapy resistance.
authors.affiliation: Graduate Institute of Clinical Medicine.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.forename: Alexander T H
authors.initials: AT
authors.lastname: Wu
authors.forename: Peter M-H
authors.initials: PM
authors.lastname: Chang
authors.forename: Kuan-Yu
authors.initials: KY
authors.lastname: Chen
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Yang
authors.forename: Shuenn-Chen
authors.initials: SC
authors.lastname: Yang
authors.forename: Chao-Chi
authors.initials: CC
authors.lastname: Ho
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Chen
authors.forename: Yu-Lun
authors.initials: YL
authors.lastname: Kuo
authors.forename: Pei-Ying
authors.initials: PY
authors.lastname: Lee
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Liu
authors.forename: Chueh-Chuan
authors.initials: CC
authors.lastname: Yen
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Jin-Mei
authors.initials: JM
authors.lastname: Lai
authors.forename: Liang-Shun
authors.initials: LS
authors.lastname: Wang
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.forename: Jeng-Fong
authors.initials: JF
authors.lastname: Chiou
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.forename: Chi-Ying F
authors.initials: CY
authors.lastname: Huang
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D000077156:Gefitinib; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011799:Quinazolines / Q000494:pharmacology*; D011897:Random Allocation; D012680:Sensitivity and Specificity; D014268:Trifluoperazine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D011799:Quinazolines; D014268:Trifluoperazine; D000077156:Gefitinib