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Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis

Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood–...

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Autores principales: Srivastava, Suyash, Zahra, Fatema Tuz, Gupta, Nehal, Tullar, Paul E., Srivastava, Sanjay K., Mikelis, Constantinos M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036977/
https://www.ncbi.nlm.nih.gov/pubmed/31979394
http://dx.doi.org/10.3390/ijms21030755
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author Srivastava, Suyash
Zahra, Fatema Tuz
Gupta, Nehal
Tullar, Paul E.
Srivastava, Sanjay K.
Mikelis, Constantinos M.
author_facet Srivastava, Suyash
Zahra, Fatema Tuz
Gupta, Nehal
Tullar, Paul E.
Srivastava, Sanjay K.
Mikelis, Constantinos M.
author_sort Srivastava, Suyash
collection PubMed
description Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood–brain barrier. Recent studies have revealed that penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by penfluridol treatment. When cancer cells were treated with the same low concentration of penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment.
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spelling pubmed-70369772020-03-11 Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis Srivastava, Suyash Zahra, Fatema Tuz Gupta, Nehal Tullar, Paul E. Srivastava, Sanjay K. Mikelis, Constantinos M. Int J Mol Sci Article Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood–brain barrier. Recent studies have revealed that penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by penfluridol treatment. When cancer cells were treated with the same low concentration of penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment. MDPI 2020-01-23 /pmc/articles/PMC7036977/ /pubmed/31979394 http://dx.doi.org/10.3390/ijms21030755 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Srivastava, Suyash
Zahra, Fatema Tuz
Gupta, Nehal
Tullar, Paul E.
Srivastava, Sanjay K.
Mikelis, Constantinos M.
Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis
title Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis
title_full Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis
title_fullStr Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis
title_full_unstemmed Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis
title_short Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis
title_sort low dose of penfluridol inhibits vegf-induced angiogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036977/
https://www.ncbi.nlm.nih.gov/pubmed/31979394
http://dx.doi.org/10.3390/ijms21030755
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