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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.01029/full |
| _version_ | 1819268036404707328 |
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| author | Yong Xia Yong Xia Chengsen Jia Chengsen Jia Qiang Xue Jinrui Jiang Yao Xie Ranran Wang Zhiqiang Ran Fuyan Xu Yiwen Zhang Tinghong Ye |
| author_facet | Yong Xia Yong Xia Chengsen Jia Chengsen Jia Qiang Xue Jinrui Jiang Yao Xie Ranran Wang Zhiqiang Ran Fuyan Xu Yiwen Zhang Tinghong Ye |
| author_sort | Yong Xia |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-23T21:26:40Z |
| format | Article |
| id | doaj.art-689768d7bf174bff9aee18446f47654b |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-23T21:26:40Z |
| publishDate | 2019-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-689768d7bf174bff9aee18446f47654b2022-12-21T17:30:35ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-09-011010.3389/fphar.2019.01029455754Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and ApoptosisYong Xia0Yong Xia1Chengsen Jia2Chengsen Jia3Qiang Xue4Jinrui Jiang5Yao Xie6Ranran Wang7Zhiqiang Ran8Fuyan Xu9Yiwen Zhang10Tinghong Ye11Department of Rehabilitation Medicine and Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, ChinaKey Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Rehabilitation Medicine and Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, ChinaKey Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Rehabilitation Medicine and Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, ChinaWest China School of Pharmacy, Sichuan University, Chengdu, ChinaDepartment of Gynecology and Obstetrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, ChinaWest China School of Pharmacy, Sichuan University, Chengdu, ChinaWest China School of Pharmacy, Sichuan University, Chengdu, ChinaDepartment of Rehabilitation Medicine and Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, ChinaDepartment of Rehabilitation Medicine and Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, ChinaDepartment of Rehabilitation Medicine and Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, ChinaRepurposing 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.https://www.frontiersin.org/article/10.3389/fphar.2019.01029/fulltrifluoperazine hydrochloridecolorectal cancercell cycle arrestapoptosisprogrammed death-1 ligand 1 (PD-L1) |
| spellingShingle | Yong Xia Yong Xia Chengsen Jia Chengsen Jia Qiang Xue Jinrui Jiang Yao Xie Ranran Wang Zhiqiang Ran Fuyan Xu Yiwen Zhang Tinghong Ye Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis Frontiers in Pharmacology trifluoperazine hydrochloride colorectal cancer cell cycle arrest apoptosis programmed death-1 ligand 1 (PD-L1) |
| 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 | trifluoperazine hydrochloride colorectal cancer cell cycle arrest apoptosis programmed death-1 ligand 1 (PD-L1) |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.01029/full |
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