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

El-Habib Dakir,Shu-Dong Zhang,Adam Pickard,Richard Morgan,Kirtiman Srivastava,Andriana Margariti,Mohamed El-Tanani,Stephen Lloyd,Cian M Mccrudden,Stephane R Gross,Philip S Rudland

doi:10.18632/oncotarget.26175

Abstract

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.

Highlights

Antipsychotic drugs (APDs) are the first pharmacotherapeutic line of treatment for schizophrenia
Pimozide inhibits cancer cell growth in vitro and results in DNA damage To investigate whether Pimozide exerts direct anti-proliferative and pro-apoptotic effects, and causes DNA damage, we treated human invasive breast cancer MDA-MB-231, normal breast MCF10A, and lung adenocarcinoma A549 cells with this drug at different doses for 24 or 48 hours, and cell morphology was observed after 24 hours (Figure 1A)
This study is the first to report that an FDAapproved neuroleptic drug, Pimozide, which is already in clinical use, has multiple anticancer effects, since it inhibits cell proliferation, and has an anti-angiogenic www.oncotarget.com www.oncotarget.com and anti-metastatic activity

Summary

Introduction

Antipsychotic drugs (APDs) are the first pharmacotherapeutic line of treatment for schizophrenia. They are widely used for the treatment of bipolar disorder and other idiopathic psychotic disorders. Pimozide is a neuroleptic drug selectively blocks dopamine receptor D2 (DRD2) [1, 2], used to treat a number of mental/mood disorders (chronic schizophrenia), as well as other psychotic disorders, as it reduces dopamine activity and decreases excitation, agitation, hypermobility, and abnormal conditions associated with excess energy [3, 4]. It has long been suggested that patients with schizophrenia have a reduced incidence of cancer compared to the general population [5, 6]. Many epidemiological studies have been conducted to investigate this possible link, but cancer risk in schizophrenic patients remains a controversial issue [7,8,9], antipsychotic drugs have been suggested as possible mediators of this effect [5, 10, 11]

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Results

Conclusion