https://scholars.lib.ntu.edu.tw/handle/123456789/510424
標題: | Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer | 作者: | Yeh C.-T. Wu T.-H. Chang P.M.-H. KUAN-YU CHEN Yang C.-N. Yang S.-C. CHAO-CHI HO Chen C.-C. Kuo Y.-L. Lee P.-Y. Liu Y.-W. Yen C.-C. Hsiao M. Lu P.-J. Lai J.-M. Wang L.-S. Wu C.-H. Chiou J.-F. PAN-CHYR YANG Huang C.-Y.F. |
公開日期: | 2012 | 卷: | 186 | 期: | 11 | 起(迄)頁: | 1180-1188 | 來源出版物: | American Journal of Respiratory and Critical Care Medicine | 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. Copyright ? 2012 by the American Thoracic Society. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84870421832&doi=10.1164%2frccm.201207-1180OC&partnerID=40&md5=ff4d7d952e6ee72f58230f10d3744fb4 https://scholars.lib.ntu.edu.tw/handle/123456789/510424 |
ISSN: | 1073-449X | DOI: | 10.1164/rccm.201207-1180OC | SDG/關鍵字: | acepromazine; beta catenin; chlorpromazine; cisplatin; erlotinib; fluphenazine; gefitinib; perphenazine; phenothiazine; prochlorperazine; promazine; protein tyrosine kinase inhibitor; trifluoperazine; triflupromazine; Wnt protein; animal experiment; antineoplastic activity; article; cancer chemotherapy; cancer inhibition; cancer stem cell; computer model; down regulation; drug potentiation; drug screening; drug structure; embryonic stem cell; female; gene expression profiling; lung cancer; male; metastasis; mouse; multiple cycle treatment; nonhuman; priority journal; scoring system; Animals; Antipsychotic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Quinazolines; Random Allocation; Sensitivity and Specificity; Trifluoperazine; Tumor Cells, Cultured |
顯示於: | 醫學系 |
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