The anti-psychotic drug Pimozide is a Novel chemotherapeutic for Breast Cancer

Dakir El-Habib, Adam Pickard, Kirtiman Sirvastava, Cian Mc Crudden, Stephane R Gross, Stephan Llyod, Shu-Dong Zhang, Adrianna Margariti, Richard Morgan, Philip S. Rudland, Mohamed El-Tanani

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)34889-34910
JournalOncotarget
Volume9
Issue number79
DOIs
Publication statusPublished - 9 Oct 2018

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Pimozide
Breast Neoplasms
Pharmaceutical Preparations
Lung Neoplasms
Down-Regulation
Vascular Endothelial Growth Factor Receptor-2
Neoplasms
Epithelial-Mesenchymal Transition
Myofibroblasts
Double-Stranded DNA Breaks
GTP Phosphohydrolases
Stromal Cells
Cell Cycle Checkpoints
Matrix Metalloproteinases
Heterografts
Antipsychotic Agents
Cell Movement
Smooth Muscle
Actins
Breast

Bibliographical note

© Dakir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0
(CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source
are credited.

Keywords

  • Pimozide, Breast cancer, Apoptosis, Xenograft, Ran, VEGFR2

Cite this

El-Habib, D., Pickard, A., Sirvastava, K., Mc Crudden, C., Gross, S. R., Llyod, S., ... El-Tanani, M. (2018). The anti-psychotic drug Pimozide is a Novel chemotherapeutic for Breast Cancer. Oncotarget, 9(79), 34889-34910. https://doi.org/10.18632/oncotarget.26175
El-Habib, Dakir ; Pickard, Adam ; Sirvastava, Kirtiman ; Mc Crudden, Cian ; Gross, Stephane R ; Llyod, Stephan ; Zhang, Shu-Dong ; Margariti, Adrianna ; Morgan, Richard ; Rudland, Philip S. ; El-Tanani, Mohamed. / The anti-psychotic drug Pimozide is a Novel chemotherapeutic for Breast Cancer. In: Oncotarget. 2018 ; Vol. 9, No. 79. pp. 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 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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El-Habib, D, Pickard, A, Sirvastava, K, Mc Crudden, C, Gross, SR, Llyod, S, Zhang, S-D, Margariti, A, Morgan, R, Rudland, PS & El-Tanani, M 2018, 'The anti-psychotic drug Pimozide is a Novel chemotherapeutic for Breast Cancer', Oncotarget, vol. 9, no. 79, pp. 34889-34910. https://doi.org/10.18632/oncotarget.26175

The anti-psychotic drug Pimozide is a Novel chemotherapeutic for Breast Cancer. / El-Habib, Dakir; Pickard, Adam; Sirvastava, Kirtiman; Mc Crudden, Cian; Gross, Stephane R; Llyod, Stephan; Zhang, Shu-Dong; Margariti, Adrianna ; Morgan, Richard; Rudland, Philip S.; El-Tanani, Mohamed.

In: Oncotarget, Vol. 9, No. 79, 09.10.2018, p. 34889-34910.

Research output: Contribution to journalArticle

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AU - El-Habib, Dakir

AU - Pickard, Adam

AU - Sirvastava, Kirtiman

AU - Mc Crudden, Cian

AU - Gross, Stephane R

AU - Llyod, Stephan

AU - Zhang, Shu-Dong

AU - Margariti, Adrianna

AU - Morgan, Richard

AU - Rudland, Philip S.

AU - El-Tanani, Mohamed

N1 - © Dakir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Y1 - 2018/10/9

N2 - 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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El-Habib D, Pickard A, Sirvastava K, Mc Crudden C, Gross SR, Llyod S et al. The anti-psychotic drug Pimozide is a Novel chemotherapeutic for Breast Cancer. Oncotarget. 2018 Oct 9;9(79):34889-34910. https://doi.org/10.18632/oncotarget.26175