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

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 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: 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
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 186 Issue 11 Pg. 1180-8 (Dec 01 2012) ISSN: 1535-4970 [Electronic] United States
• PMID: 23024022 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Quinazolines
• Trifluoperazine
• Gefitinib

Topics

• Animals
• Antipsychotic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm
• Gefitinib
• Lung Neoplasms (drug therapy, pathology)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplastic Stem Cells (drug effects)
• Quinazolines (pharmacology)
• Random Allocation
• Sensitivity and Specificity
• Trifluoperazine (pharmacology)
• Tumor Cells, Cultured (drug effects)