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

Abstract

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.

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension

“…Interestingly, various mechanisms seem to account for the anti-tumor effects of TFP [ 11 , 12 , 13 , 14 , 15 , 18 ]. In addition to inhibiting calmodulin and downregulating AKT activity, TFP was reported to inhibit DNA repair efficiency in cancer cells by decreasing expression of several DNA repair proteins including RAD51 [ 19 , 37 , 38 ], found to be upregulated in PAH cells [ 39 ].…”

“…Besides the development of new compounds, drug repurposing/repositioning has become an attractive strategy to treat cancer and PAH [ 9 , 10 ], taking advantage of the well-known safety and pharmacokinetics profiles of drugs already in use for a disease to treat another illness and, thus, expedite therapies to the clinic. The antipsychotic drug trifluoperazine (TFP) was recently repurposed for cancer treatment due to its anti-tumor activity in various preclinical models [ 11 , 12 , 13 , 14 , 15 ]. Although the exact mechanism of action of TFP remains unclear, TFP was initially shown to inhibit dopamine receptors and functions as an antagonist of calmodulin, a key regulator of calcium-dependent signal transduction critically implicated in vascular smooth muscle cell contraction and proliferation [ 16 , 17 ].…”

Quantitative proteomics identifies secreted diagnostic biomarkers as well as tumor-dependent prognostic targets for clear cell Renal Cell Carcinoma

“…One highly elevated EMT marker in cluster 1 tumors is the signaling protein S100A4, which is a target of the antipsychotic drug trifluoperazine (Figure 7A). It has been shown that trifluoperazine can be repurposed as an anticancer drug and successfully prevent or minimize metastatic spread in different cancers by inhibiting S100A4 through protein oligomerization (55, 56). Targeting S100A4 could also be advantageous for reducing hypoxic signaling in cluster 1 tumors, since it was revealed as HIF1α target (Supplementary File 3).…”

Refocusing the Use of Psychiatric Drugs for Treatment of Gastrointestinal Cancers

“…Trifluoperazine, an anti-psychotic, inhibits cell viability and proliferation, induces apoptosis and promotes cell arrest at G0/G1 phase by repressing CDK2, CDK4, cyclin D1, cyclin E through the increasing p27 expression on HCT116. Also, this effect has a synergized effect with 5-fluorouracil and Oxaliplatin in CT26 and HCT116 colorectal cancer cells (22,23).…”