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

研究成果: 雜誌貢獻文章

103 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)1180-1188
頁數9
期刊American Journal of Respiratory and Critical Care Medicine
186
發行號11
DOIs
出版狀態已發佈 - 十二月 1 2012

指紋

Trifluoperazine
Neoplastic Stem Cells
Drug Resistance
Antipsychotic Agents
Lung Neoplasms
Growth
Cisplatin
Lung
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Catenins
Embryonic Stem Cells
Transcriptome
Pharmaceutical Preparations
Neoplasms
Animal Models
gefitinib
Recurrence
Drug Therapy

ASJC Scopus subject areas

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

引用此文

Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. / Yeh, Chi-Tai; Wu, Alexander T H; Chang, Peter M H; Chen, Kuan Yu; Yang, Chia Ning; Yang, Shuenn Chen; Ho, Chao Chi; Chen, Chun Chi; Kuo, Yu Lun; Lee, Pei Ying; Liu, Yu Wen; Yen, Chueh Chuan; Hsiao, Michael; Lu, Pei Jung; Lai, Jin Mei; Wang, Liang Shun; Wu, Chih Hsiung; Chiou, Jeng Fong; Yang, Pan Chyr; Huang, Chi Ying F.

於: American Journal of Respiratory and Critical Care Medicine, 卷 186, 編號 11, 01.12.2012, p. 1180-1188.

研究成果: 雜誌貢獻文章

Yeh, C-T, Wu, ATH, Chang, PMH, Chen, KY, Yang, CN, Yang, SC, Ho, CC, Chen, CC, Kuo, YL, Lee, PY, Liu, YW, Yen, CC, Hsiao, M, Lu, PJ, Lai, JM, Wang, LS, Wu, CH, Chiou, JF, Yang, PC & Huang, CYF 2012, 'Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer', American Journal of Respiratory and Critical Care Medicine, 卷 186, 編號 11, 頁 1180-1188. https://doi.org/10.1164/rccm.201207-1180OC
Yeh, Chi-Tai ; Wu, Alexander T H ; Chang, Peter M H ; Chen, Kuan Yu ; Yang, Chia Ning ; Yang, Shuenn Chen ; Ho, Chao Chi ; Chen, Chun Chi ; Kuo, Yu Lun ; Lee, Pei Ying ; Liu, Yu Wen ; Yen, Chueh Chuan ; Hsiao, Michael ; Lu, Pei Jung ; Lai, Jin Mei ; Wang, Liang Shun ; Wu, Chih Hsiung ; Chiou, Jeng Fong ; Yang, Pan Chyr ; Huang, Chi Ying F. / Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. 於: American Journal of Respiratory and Critical Care Medicine. 2012 ; 卷 186, 編號 11. 頁 1180-1188.
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AU - Chen, Kuan Yu

AU - Yang, Chia Ning

AU - Yang, Shuenn Chen

AU - Ho, Chao Chi

AU - Chen, Chun Chi

AU - Kuo, Yu Lun

AU - Lee, Pei Ying

AU - Liu, Yu Wen

AU - Yen, Chueh Chuan

AU - Hsiao, Michael

AU - Lu, Pei Jung

AU - Lai, Jin Mei

AU - Wang, Liang Shun

AU - Wu, Chih Hsiung

AU - Chiou, Jeng Fong

AU - Yang, Pan Chyr

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