The anti-psychotic drug pimozide is a novel chemotherapeutic for breast cancer
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EL-Habib Dakir1,2,8, Adam Pickard1, Kirtiman Srivastava1, Cian M. McCrudden3, Stephane R. Gross4, Stephen Lloyd5, Shu-Dong Zhang6, Andriana Margariti7, Richard Morgan8, Philip S. Rudland9 and Mohamed El-Tanani8
1Center for Cancer Research and Cell Biology, Queen’s University, Belfast, UK
2Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Salamanca, Salamanca, Spain
3School of Pharmacy, Queen’s University Belfast, Belfast, UK
4School of Life and Health Sciences, Aston University, Birmingham, UK
5School of Medicine, Animal Facility, Queen’s University Belfast, Belfast, UK
6Northern Ireland Centre for Stratified Medicine, Biomedical Sciences, University of Ulster, UK
7Center of Experimental Medicine, Queen’s University Belfast, Belfast, UK
8Institute of Cancer Therapeutics, University of Bradford, Bradford, UK
9Institute of integrative Biology, University of Liverpool, Liverpool, UK
EL-Habib Dakir, email: [email protected]
Mohamed El-Tanani, email: [email protected]
Keywords: pimozide; breast cancer; DSB; apoptosis; xenograft
Received: February 28, 2018 Accepted: September 04, 2018 Published: October 09, 2018
Pimozide, an antipsychotic drug of the diphenylbutylpiperidine class, has been shown to suppress cell growth of breast cancer cells in vitro. In this study we further explore the inhibitory effects of this molecule in cancer cells. We found that Pimozide inhibited cell proliferation in a dose- and time-dependent manner in MDA-MB-231 breast cancer cells and A549 lung cancer cells. Furthermore, we found that Pimozide also promoted apoptosis as demonstrated by cell cycle arrest and induction of double-strand DNA breaks but did not result in any effect in the non-transformed MCF10A breast cell line. In order to shed new lights into the molecular pathways affected by Pimozide, we show that Pimozide downregulated RAN GTPase and AKT at both protein and mRNA levels and inhibited the AKT signaling pathway in MDA-MB-231 breast cancer cells. Pimozide also inhibited the epithelial mesenchymal transition and cell migration and downregulated the expression of MMPs. Administration of Pimozide showed a potent in vivo antitumor activity in MDA-MB-231 xenograft animal model and reduced the number of lung metastases by blocking vascular endothelial growth factor receptor 2. Furthermore, Pimozide inhibited myofibroblast formation as evaluated by the reduction in α-smooth muscle actin containing cells. Thus, Pimozide might inhibit tumor development by suppressing angiogenesis and by paracrine stimulation provided by host reactive stromal cells. These results demonstrate a novel in vitro and in vivo antitumor activity of Pimozide against breast and lung cancer cells and provide the proof of concept for a putative Pimozide as a novel approach for cancer therapy.
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