Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer

Chi-Tai Yeh, Alexander T H Wu, Peter M H Chang, Kuan Yu Chen, Chia Ning Yang, Shuenn Chen Yang, Chao Chi Ho, Chun Chi Chen, Yu Lun Kuo, Pei Ying Lee, Yu Wen Liu, Chueh Chuan Yen, Michael Hsiao, Pei Jung Lu, Jin Mei Lai, Liang Shun Wang, Chih Hsiung Wu, Jeng Fong Chiou, Pan Chyr Yang, Chi Ying F Huang

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Rationale: Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance. Objectives: 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. Measurements and Main 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 cancermetastatic and orthotopic CSC animalmodels. Conclusions:Usingin silicodrugscreeningbyConnectivityMapfollowed 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.

Original languageEnglish
Pages (from-to)1180-1188
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume186
Issue number11
DOIs
Publication statusPublished - Dec 1 2012

Keywords

  • Cancer stem cell
  • Connectivity map
  • Gefitinib
  • Lung cancer
  • Trifluoperazine

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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