title: Repurposing the antipsychotic trifluoperazine as an antimetastasis agent.
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.
authors.affiliation: Department 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.).
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Pulkoski-Gross
authors.affiliation: Department 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.).
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department 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.).
authors.forename: Carolina
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Department 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.).
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department 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.).
authors.forename: Nengtai
authors.initials: N
authors.lastname: Ouyang
authors.affiliation: Department 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.).
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
authors.affiliation: Department 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.).
authors.forename: Stanley
authors.initials: S
authors.lastname: Zucker
authors.affiliation: Department 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.) jian.cao@sunysb.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002642:Chick Embryo; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D014268:Trifluoperazine / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D014150:Antipsychotic Agents; D014268:Trifluoperazine