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Front. Pharmacol. | doi: 10.3389/fphar.2019.01029

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

 Tinghong Ye1*,  Yong Xia1, Chengsen Jia1, Qiang Xue1, Jinrui Jiang2, Yao Xie3, Ranran Wang2,  Zhiqiang Ran2, Fuyan Xu1 and  Yiwen Zhang1
  • 1State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China
  • 2West China School of Pharmacy, Sichuan University, China
  • 3Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, China

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.

Keywords: Trifluoperazine hydrochloride (TFP HCL), colorectal cancer, cell cycle arrest, Apoptosis, programmed death-1 ligand 1 (PD-L1)

Received: 21 Feb 2019; Accepted: 12 Aug 2019.

Copyright: © 2019 Ye, Xia, Jia, Xue, Jiang, Xie, Wang, Ran, Xu and Zhang. 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.

* Correspondence: Dr. Tinghong Ye, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China,