American journal of respiratory and critical care medicine, 2012-12, Vol.186 (11), p.1180-1188
2012
Details
- Autor(en) / Beteiligte
- Titel
- Trifluoperazine, an Antipsychotic Agent, Inhibits Cancer Stem Cell Growth and Overcomes Drug Resistance of Lung Cancer
- Ist Teil von
- American journal of respiratory and critical care medicine, 2012-12, Vol.186 (11), p.1180-1188
- Ort / Verlag
- New York, NY: American Thoracic Society
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek (Open access)
- Beschreibungen/Notizen
- Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance. To screen drugs that target CSCs to improve the current treatment outcome and overcome drug resistance in patients with lung cancer. 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. 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1073-449XeISSN: 1535-4970DOI: 10.1164/rccm.201207-1180ocTitel-ID: cdi_proquest_miscellaneous_1221858927
- Format
- –
- Schlagworte
- Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy, Animals, Antipsychotic Agents - pharmacology, Apoptosis - drug effects, Biological and medical sciences, Carcinoma, Non-Small-Cell Lung - drug therapy, Carcinoma, Non-Small-Cell Lung - pathology, Cell Proliferation - drug effects, Clinical death. Palliative care. Organ gift and preservation, Disease Models, Animal, Drug Resistance, Neoplasm, Intensive care medicine, Lung cancer, Lung Neoplasms - drug therapy, Lung Neoplasms - pathology, Medical sciences, 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