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Repurposing the antipsychotic trifluoperazine as an antimetastasis agent
#MMPMID25552486
Pulkoski-Gross A
; Li J
; Zheng C
; Li Y
; Ouyang N
; Rigas B
; Zucker S
; Cao J
Mol Pharmacol
2015[]; 87
(3
): 501-12
PMID25552486
show ga
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 ?-catenin (Ser(552)).
Lack of phosphorylation of Ser(552) of ?-catenin prevents ?-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 ?-catenin pathway and propose that trifluoperazine may be used as an
antimetastasis chemotherapeutic.
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