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Published on: April 25, 2025
Repurposing the antipsychotic trifluoperazine as an antimetastasis agent
Ashleigh Pulkoski-Gross1, Jian Li1, Carolina Zheng1
1Department of Pharmacological Sciences/Cancer Prevention (A.P.G.), Department of Medicine/Cancer Prevention (C.Z., Y.L., B.R., J.C.), and Department of Medicine/Hematology & Oncology (S.Z.), Stony Brook University, Stony Brook, New York; Jimei University, Xiamen, China (J.L.); and Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, China (N.O.).
Abstract:
Because cancer cell invasion is a critical determinant of metastasis, targeting invasion is a viable approach to prevent metastasis. Utilizing a novel three-dimensional high-throughput invasion assay, we screened a National Cancer Institute compound library and discovered compounds demonstrating inhibitory effects on cancer cell invasion. One hit, trifluoperazine, suppresses invasion of human cancer cell lines while displaying a limited cytotoxicity profile. This inhibition is due to the interference with cancer cell migratory ability but not proteolytic activity. Treatment of cancer cells with trifluoperazine significantly reduces angiogenesis and prevents cancer cell invasion through a chorioallantoic basement membrane. Mechanistically, treatment results in decreased phosphorylated AKT (Ser(473) and Thr(308)) and β-catenin (Ser(552)). Lack of phosphorylation of Ser(552) of β-catenin prevents β-catenin nuclear relocation, resulting in decreased expression of vascular endothelial growth factor, likely mediated through dopamine receptor D2. Taken together, we demonstrated that trifluoperazine is responsible for reducing the angiogenic and invasive potential of aggressive cancer cells through dopamine receptor D2 to modulate the β-catenin pathway and propose that trifluoperazine may be used as an antimetastasis chemotherapeutic.
Insights
Trifluoperazine, an anti-cancer drug, effectively inhibits cancer cell invasion and metastasis by impacting cell migration and angiogenesis. This compound shows potential as a novel chemotherapeutic agent for preventing cancer spread.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Cancer cell invasion is a key factor in metastasis.
- Targeting cancer cell invasion offers a strategy to prevent metastasis.
Purpose of the Study:
- To identify compounds that inhibit cancer cell invasion using a novel high-throughput assay.
- To investigate the antimetastatic potential of trifluoperazine.
Main Methods:
- Screening of the National Cancer Institute compound library using a 3D high-throughput invasion assay.
- Assessing the effects of trifluoperazine on cancer cell invasion, migration, and proteolytic activity.
- Evaluating the impact of trifluoperazine on angiogenesis and metastasis in vivo.
- Analyzing molecular mechanisms involving AKT, β-catenin, and vascular endothelial growth factor (VEGF) signaling pathways.
Main Results:
- Trifluoperazine significantly suppressed the invasion of human cancer cell lines with limited cytotoxicity.
- Inhibition of invasion was attributed to reduced cancer cell migratory ability, not proteolytic activity.
- Trifluoperazine treatment decreased angiogenesis and prevented cancer cell invasion through a chorioallantoic basement membrane.
- Mechanistically, trifluoperazine reduced phosphorylated AKT and β-catenin, leading to decreased VEGF expression, likely mediated by dopamine receptor D2.
Conclusions:
- Trifluoperazine reduces the angiogenic and invasive potential of aggressive cancer cells.
- The mechanism involves the modulation of the β-catenin pathway via dopamine receptor D2.
- Trifluoperazine shows promise as an antimetastasis chemotherapeutic agent.
