{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:19:34Z","timestamp":1790327974467,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2012,12,1]],"date-time":"2012-12-01T00:00:00Z","timestamp":1354320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To screen drugs that target CSCs to improve the current treatment outcome and overcome drug resistance in patients with lung cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2013tyrosine 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44\/CD133). Trifluoperazine inhibited Wnt\/\u03b2-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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\u2013tyrosine kinase inhibitor and chemotherapy resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201207-1180oc","type":"journal-article","created":{"date-parts":[[2012,9,30]],"date-time":"2012-09-30T22:09:35Z","timestamp":1349042975000},"page":"1180-1188","source":"Crossref","is-referenced-by-count":178,"title":["Trifluoperazine, an Antipsychotic Agent, Inhibits Cancer Stem Cell Growth and Overcomes Drug Resistance of Lung Cancer"],"prefix":"10.1093","volume":"186","author":[{"given":"Chi-Tai","family":"Yeh","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medicine"},{"name":"Department of Surgery, and"},{"name":"Center of Excellence for Cancer Research, and"},{"name":"Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander T. 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and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Ying","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chueh-Chuan","family":"Yen","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Genomics Research Center, Academia Sinica, Taipei, 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