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Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis

Repurposing existing drugs for cancer treatment is an effective strategy. An approved antipsychotic drug, trifluoperazine (TFP), has been reported to have potential anticancer effects against several cancer types. Here, we investigated the effect and molecular mechanism of TFP in colorectal cancer (...

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Autores principales: Xia, Yong, Jia, Chengsen, Xue, Qiang, Jiang, Jinrui, Xie, Yao, Wang, Ranran, Ran, Zhiqiang, Xu, Fuyan, Zhang, Yiwen, Ye, Tinghong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753363/
https://www.ncbi.nlm.nih.gov/pubmed/31572198
http://dx.doi.org/10.3389/fphar.2019.01029
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author Xia, Yong
Jia, Chengsen
Xue, Qiang
Jiang, Jinrui
Xie, Yao
Wang, Ranran
Ran, Zhiqiang
Xu, Fuyan
Zhang, Yiwen
Ye, Tinghong
author_facet Xia, Yong
Jia, Chengsen
Xue, Qiang
Jiang, Jinrui
Xie, Yao
Wang, Ranran
Ran, Zhiqiang
Xu, Fuyan
Zhang, Yiwen
Ye, Tinghong
author_sort Xia, Yong
collection PubMed
description Repurposing existing drugs for cancer treatment is an effective strategy. An approved antipsychotic drug, trifluoperazine (TFP), has been reported to have potential anticancer effects against several cancer types. Here, we investigated the effect and molecular mechanism of TFP in colorectal cancer (CRC). In vitro studies showed that TFP induced G0/G1 cell cycle arrest to dramatically inhibit CRC cell proliferation through downregulating cyclin-dependent kinase (CDK) 2, CDK4, cyclin D1, and cyclin E and upregulating p27. TFP also induced apoptosis, decreased mitochondrial membrane potential, and increased reactive oxygen species levels in CRC cells, indicating that TFP induced mitochondria-mediated intrinsic apoptosis. Importantly, TFP significantly suppressed tumor growth in two CRC subcutaneous tumor models without side effects. Interestingly, TFP treatment increased the expression levels of programmed death-1 ligand 1 (PD-L1) in CRC cells and programmed death-1 (PD-1) in tumor-infiltrating CD4+ and CD8+ T cells, implying that the combination of TFP with an immune checkpoint inhibitor, such as an anti-PD-L1 or anti-PD-1 antibody, might have synergistic anticancer effects. Taken together, our study signifies that TFP is a novel treatment strategy for CRC and indicates the potential for using the combination treatment of TFP and immune checkpoint blockade to increase antitumor efficiency.
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spelling pubmed-67533632019-09-30 Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis Xia, Yong Jia, Chengsen Xue, Qiang Jiang, Jinrui Xie, Yao Wang, Ranran Ran, Zhiqiang Xu, Fuyan Zhang, Yiwen Ye, Tinghong Front Pharmacol Pharmacology Repurposing existing drugs for cancer treatment is an effective strategy. An approved antipsychotic drug, trifluoperazine (TFP), has been reported to have potential anticancer effects against several cancer types. Here, we investigated the effect and molecular mechanism of TFP in colorectal cancer (CRC). In vitro studies showed that TFP induced G0/G1 cell cycle arrest to dramatically inhibit CRC cell proliferation through downregulating cyclin-dependent kinase (CDK) 2, CDK4, cyclin D1, and cyclin E and upregulating p27. TFP also induced apoptosis, decreased mitochondrial membrane potential, and increased reactive oxygen species levels in CRC cells, indicating that TFP induced mitochondria-mediated intrinsic apoptosis. Importantly, TFP significantly suppressed tumor growth in two CRC subcutaneous tumor models without side effects. Interestingly, TFP treatment increased the expression levels of programmed death-1 ligand 1 (PD-L1) in CRC cells and programmed death-1 (PD-1) in tumor-infiltrating CD4+ and CD8+ T cells, implying that the combination of TFP with an immune checkpoint inhibitor, such as an anti-PD-L1 or anti-PD-1 antibody, might have synergistic anticancer effects. Taken together, our study signifies that TFP is a novel treatment strategy for CRC and indicates the potential for using the combination treatment of TFP and immune checkpoint blockade to increase antitumor efficiency. Frontiers Media S.A. 2019-09-13 /pmc/articles/PMC6753363/ /pubmed/31572198 http://dx.doi.org/10.3389/fphar.2019.01029 Text en Copyright © 2019 Xia, Jia, Xue, Jiang, Xie, Wang, Ran, Xu, Zhang and Ye http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Xia, Yong
Jia, Chengsen
Xue, Qiang
Jiang, Jinrui
Xie, Yao
Wang, Ranran
Ran, Zhiqiang
Xu, Fuyan
Zhang, Yiwen
Ye, Tinghong
Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis
title Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis
title_full Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis
title_fullStr Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis
title_full_unstemmed Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis
title_short Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis
title_sort antipsychotic drug trifluoperazine suppresses colorectal cancer by inducing g0/g1 arrest and apoptosis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753363/
https://www.ncbi.nlm.nih.gov/pubmed/31572198
http://dx.doi.org/10.3389/fphar.2019.01029
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