Journal
FRONTIERS IN PHARMACOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2019.01029
Keywords
trifluoperazine hydrochloride; colorectal cancer; cell cycle arrest; apoptosis; programmed death-1 ligand 1 (PD-L1)
Categories
Funding
- National Natural Science Foundation of China [81702898, 81602950]
- China Postdoctoral Science Foundation [2018T110981, 2017M612977]
- Fundamental Research Funds for the Central Universities (Postdoctoral Foundation of Sichuan University) [2017SCU12046]
- Post-Doctor Research Project, West China Hospital, Sichuan University [2019HXBH017]
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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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