RT Journal Article
SR Electronic
T1 Repurposing the Anti-psychotic Trifluoperazine as an Anti-metastasis Agent
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.096941
DO 10.1124/mol.114.096941
A1 Ashleigh E. Pulkoski-Gross
A1 Jian Li
A1 Carolina Zheng
A1 Yiyi Li
A1 Nengtai Ouyang
A1 Basil Rigas
A1 Stanley Zucker
A1 Jian Cao
YR 2014
UL http://molpharm.aspetjournals.org/content/early/2014/12/31/mol.114.096941.abstract
AB Since 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 (Ser473 and Thr308) and β-catenin (Ser552). Lack of phosphorylation of Ser552 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 have 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 anti-metastasis chemotherapeutic.