{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:46:59Z","timestamp":1779338819851,"version":"3.51.4"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,13]],"date-time":"2021-03-13T00:00:00Z","timestamp":1615593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen\/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.<\/jats:p>","DOI":"10.3390\/ijms22062919","type":"journal-article","created":{"date-parts":[[2021,3,14]],"date-time":"2021-03-14T22:13:10Z","timestamp":1615759990000},"page":"2919","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension"],"prefix":"10.3390","volume":"22","author":[{"given":"Yann","family":"Grobs","sequence":"first","affiliation":[{"name":"Pulmonary Hypertension Research Group, Qu\u00e9bec Heart and Lung Institute Research Centre, Qu\u00e9bec City, QC G1V 4G5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charifa","family":"Awada","sequence":"additional","affiliation":[{"name":"Pulmonary 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Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1177\/2045893217701438","article-title":"The cancer theory of pulmonary arterial hypertension","volume":"7","author":"Boucherat","year":"2017","journal-title":"Pulm. Circ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1801887","DOI":"10.1183\/13993003.01887-2018","article-title":"Pathology and pathobiology of pulmonary hypertension: State of the art and research perspectives","volume":"53","author":"Humbert","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/j.jacbts.2020.07.011","article-title":"Treatment Targets for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension","volume":"5","author":"Prisco","year":"2020","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/S2213-2600(16)00027-8","article-title":"Combination therapy versus monotherapy for pulmonary arterial hypertension: A meta-analysis","volume":"4","author":"Lajoie","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1164\/rccm.201606-1226PP","article-title":"Translational Advances in the Field of Pulmonary Hypertension. From Cancer Biology to New Pulmonary Arterial Hypertension Therapeutics. Targeting Cell Growth and Proliferation Signaling Hubs","volume":"195","author":"Pullamsetti","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1097\/FJC.0000000000000014","article-title":"Inhibition of phosphatidylinositol 3-kinase\/Akt signaling attenuates hypoxia-induced pulmonary artery remodeling and suppresses CREB depletion in arterial smooth muscle cells","volume":"62","author":"Garat","year":"2013","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"L354","DOI":"10.1152\/ajplung.00010.2002","article-title":"PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells","volume":"283","author":"Goncharova","year":"2002","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2045894019832226","DOI":"10.1177\/2045894019832226","article-title":"Drug repositioning in pulmonary arterial hypertension: Challenges and opportunities","volume":"9","author":"Grinnan","year":"2019","journal-title":"Pulm. Circ."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41392-020-00213-8","article-title":"Overcoming cancer therapeutic bottleneck by drug repurposing","volume":"5","author":"Zhang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"27540","DOI":"10.1038\/srep27540","article-title":"Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents-A drug repurposing strategy","volume":"6","author":"Wu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"42110","DOI":"10.18632\/oncotarget.9881","article-title":"Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo","volume":"7","author":"Park","year":"2016","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1158\/1535-7163.MCT-16-0169-T","article-title":"Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R","volume":"16","author":"Kang","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.3389\/fphar.2019.01029","article-title":"Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0\/G1 Arrest and Apoptosis","volume":"10","author":"Xia","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Huang, C., Lan, W., Fraunhoffer, N., Meilerman, A., Iovanna, J., and Santofimia-Castano, P. (2019). Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma. Cancers, 11.","DOI":"10.3390\/cancers11121869"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/nsb1194-795","article-title":"Trifluoperazine-induced conformational change in Ca2+-calmodulin","volume":"1","author":"Vandonselaar","year":"1994","journal-title":"Nat. Struct. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nrcardio.2011.87","article-title":"Mechanisms of disease: Pulmonary arterial hypertension","volume":"8","author":"Schermuly","year":"2011","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105295","DOI":"10.1016\/j.phrs.2020.105295","article-title":"Repurposing of antipsychotic trifluoperazine for treating brain metastasis, lung metastasis and bone metastasis of melanoma by disrupting autophagy flux","volume":"163","author":"Xia","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s13046-017-0588-z","article-title":"Trifluoperazine, a novel autophagy inhibitor, increases radiosensitivity in glioblastoma by impairing homologous recombination","volume":"36","author":"Zhang","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1164\/rccm.201708-1751OC","article-title":"Mitochondrial HSP90 Accumulation Promotes Vascular Remodeling in Pulmonary Arterial Hypertension","volume":"198","author":"Boucherat","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1161\/CIRCULATIONAHA.109.916098","article-title":"Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: A basis for excessive cell proliferation and a new therapeutic target","volume":"121","author":"Archer","year":"2010","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/35008115","article-title":"AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1","volume":"404","author":"Medema","year":"2000","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature01036","article-title":"Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress","volume":"419","author":"Kops","year":"2002","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1016\/j.neurobiolaging.2014.01.027","article-title":"Trifluoperazine rescues human dopaminergic cells from wild-type alpha-synuclein-induced toxicity","volume":"35","author":"Hollerhage","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1002\/2211-5463.12960","article-title":"Trifluoperazine induces cellular apoptosis by inhibiting autophagy and targeting NUPR1 in multiple myeloma","volume":"10","author":"Li","year":"2020","journal-title":"FEBS Open Bio"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.cell.2010.01.028","article-title":"Methods in mammalian autophagy research","volume":"140","author":"Mizushima","year":"2010","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1146\/annurev-biochem-060815-014556","article-title":"Mammalian Autophagy: How Does It Work?","volume":"85","author":"Bento","year":"2016","journal-title":"Annu. Rev. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1093\/cvr\/cvp425","article-title":"Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation","volume":"86","author":"Furgeson","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.yexmp.2010.04.002","article-title":"Insulin-like growth factor-1 induces phosphorylation of PI3K-Akt\/PKB to potentiate proliferation of smooth muscle cells in human saphenous vein","volume":"89","author":"Jia","year":"2010","journal-title":"Exp. Mol. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/nm.3695","article-title":"Pro-proliferative and inflammatory signaling converge on FoxO1 transcription factor in pulmonary hypertension","volume":"20","author":"Savai","year":"2014","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1038\/onc.2008.24","article-title":"FOXOs, cancer and regulation of apoptosis","volume":"27","author":"Fu","year":"2008","journal-title":"Oncogene"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","article-title":"Autophagy in the pathogenesis of disease","volume":"132","author":"Levine","year":"2008","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1038\/s41419-018-1046-3","article-title":"The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0\/G1 arrest and apoptosis","volume":"9","author":"Feng","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.chembiol.2017.03.005","article-title":"Rescue of Pink1 Deficiency by Stress-Dependent Activation of Autophagy","volume":"24","author":"Zhang","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15756","DOI":"10.1002\/jcb.28845","article-title":"Trifluoperazine as an alternative strategy for the inhibition of tumor growth of colorectal cancer","volume":"120","author":"Qian","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1161\/CIRCRESAHA.111.300483","article-title":"Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type II receptor degradation","volume":"112","author":"Long","year":"2013","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1158\/1535-7163.MCT-06-0402","article-title":"The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non small cell lung carcinoma cells to DNA double-strand break induced cell death","volume":"6","author":"Polischouk","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.mrgentox.2007.05.011","article-title":"Trifluoperazine stimulates ionizing radiation induced cell killing through inhibition of DNA repair","volume":"633","author":"Gangopadhyay","year":"2007","journal-title":"Mutat. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1161\/ATVBAHA.119.312537","article-title":"Inhibition of CHK 1 (Checkpoint Kinase 1) Elicits Therapeutic Effects in Pulmonary Arterial Hypertension","volume":"39","author":"Bourgeois","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1161\/CIRCULATIONAHA.113.006167","article-title":"Role for DNA damage signaling in pulmonary arterial hypertension","volume":"129","author":"Meloche","year":"2014","journal-title":"Circulation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0022-5223(19)35334-6","article-title":"Improvement of myocardial function by trifluoperazine, a calmodulin antagonist, after acute coronary artery occlusion and coronary revascularization","volume":"97","author":"Otani","year":"1989","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00109-017-1619-0","article-title":"FOXM1 promotes pulmonary artery smooth muscle cell expansion in pulmonary arterial hypertension","volume":"96","author":"Bourgeois","year":"2018","journal-title":"J. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1161\/CIRCRESAHA.117.312579","article-title":"Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research","volume":"122","author":"Provencher","year":"2018","journal-title":"Circ. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1164\/rccm.201607-1515PP","article-title":"Translating Research into Improved Patient Care in Pulmonary Arterial Hypertension","volume":"195","author":"Bonnet","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1161\/CIRCULATIONAHA.120.047626","article-title":"Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension","volume":"142","author":"Omura","year":"2020","journal-title":"Circulation"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/2919\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:35:14Z","timestamp":1760160914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/6\/2919"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,13]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22062919"],"URL":"https:\/\/doi.org\/10.3390\/ijms22062919","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,13]]}}}