The anti-psychotic drug pimozide is a novel chemotherapeutic for breast cancer.



Dakir, El-Habib, Pickard, Adam, Srivastava, Kirtiman, McCrudden, Cian M, Gross, Stephane R ORCID: 0000-0002-0867-8866, Lloyd, Stephen, Zhang, Shu-Dong, Margariti, Andriana, Morgan, Richard, Rudland, Philip S ORCID: 0000-0002-7491-0846
et al (show 1 more authors) (2018) The anti-psychotic drug pimozide is a novel chemotherapeutic for breast cancer. Oncotarget, 9 (79). 34889 - 34910.

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Abstract

Pimozide, an antipsychotic drug of the diphenylbutylpiperidine class, has been shown to suppress cell growth of breast cancer cells <i>in vitro</i>. 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 <i>in vivo</i> 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 <i>in vitro</i> and <i>in vivo</i> 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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 28 Feb 2019 16:31
Last Modified: 08 Jun 2022 07:10
DOI: 10.18632/oncotarget.26175
Open Access URL: https://doi.org/10.18632/oncotarget.26175
URI: https://livrepository.liverpool.ac.uk/id/eprint/3033602