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Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types
Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti‐angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899631/ https://www.ncbi.nlm.nih.gov/pubmed/36156330 http://dx.doi.org/10.1111/cas.15602 |
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author | Liu, Jie Wang, Huxia Zhang, Miao Li, Yazhao Wang, Ruiqi Chen, He Wang, Bo Gao, Xiaoqian Song, Shaoran Wang, Yaochun Ren, Yu Li, Juan Liu, Peijun |
author_facet | Liu, Jie Wang, Huxia Zhang, Miao Li, Yazhao Wang, Ruiqi Chen, He Wang, Bo Gao, Xiaoqian Song, Shaoran Wang, Yaochun Ren, Yu Li, Juan Liu, Peijun |
author_sort | Liu, Jie |
collection | PubMed |
description | Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti‐angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the underlying anticancer mechanisms of antiangiogenic drugs are still unknown. Metformin (MET) and simvastatin (SVA), two metabolic‐related drugs, have been shown to play important roles in modulating the hypoxic tumor microenvironment and angiogenesis. Whether the combination of MET and SVA could exert a more effective antitumor effect than individual treatments has not been examined. The antitumor effect of the synergism of SVA and MET was detected in mouse models, breast cancer patient‐derived organoids, and multiple tumor cell lines compared with untreated, SVA, or MET alone. RNA sequencing revealed that the combination of MET and SVA (but not MET or SVA alone) inhibited the expression of endothelin 1 (ET‐1), an important regulator of angiogenesis and the hypoxia‐related pathway. We demonstrate that the MET and SVA combination showed synergistic effects on inhibiting tumor cell proliferation, promoting apoptosis, alleviating hypoxia, decreasing angiogenesis, and increasing vessel normalization compared with the use of a single agent alone. The MET and SVA combination suppressed ET‐1‐induced hypoxia‐inducible factor 1α expression by increasing prolyl hydroxylase 2 (PHD2) expression. Furthermore, the MET and SVA combination showed a more potent anticancer effect compared with bosentan. Together, our findings suggest the potential application of the MET and SVA combination in antitumor therapy. |
format | Online Article Text |
id | pubmed-9899631 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98996312023-02-09 Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types Liu, Jie Wang, Huxia Zhang, Miao Li, Yazhao Wang, Ruiqi Chen, He Wang, Bo Gao, Xiaoqian Song, Shaoran Wang, Yaochun Ren, Yu Li, Juan Liu, Peijun Cancer Sci ORIGINAL ARTICLES Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti‐angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the underlying anticancer mechanisms of antiangiogenic drugs are still unknown. Metformin (MET) and simvastatin (SVA), two metabolic‐related drugs, have been shown to play important roles in modulating the hypoxic tumor microenvironment and angiogenesis. Whether the combination of MET and SVA could exert a more effective antitumor effect than individual treatments has not been examined. The antitumor effect of the synergism of SVA and MET was detected in mouse models, breast cancer patient‐derived organoids, and multiple tumor cell lines compared with untreated, SVA, or MET alone. RNA sequencing revealed that the combination of MET and SVA (but not MET or SVA alone) inhibited the expression of endothelin 1 (ET‐1), an important regulator of angiogenesis and the hypoxia‐related pathway. We demonstrate that the MET and SVA combination showed synergistic effects on inhibiting tumor cell proliferation, promoting apoptosis, alleviating hypoxia, decreasing angiogenesis, and increasing vessel normalization compared with the use of a single agent alone. The MET and SVA combination suppressed ET‐1‐induced hypoxia‐inducible factor 1α expression by increasing prolyl hydroxylase 2 (PHD2) expression. Furthermore, the MET and SVA combination showed a more potent anticancer effect compared with bosentan. Together, our findings suggest the potential application of the MET and SVA combination in antitumor therapy. John Wiley and Sons Inc. 2022-10-17 /pmc/articles/PMC9899631/ /pubmed/36156330 http://dx.doi.org/10.1111/cas.15602 Text en © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | ORIGINAL ARTICLES Liu, Jie Wang, Huxia Zhang, Miao Li, Yazhao Wang, Ruiqi Chen, He Wang, Bo Gao, Xiaoqian Song, Shaoran Wang, Yaochun Ren, Yu Li, Juan Liu, Peijun Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types |
title | Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types |
title_full | Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types |
title_fullStr | Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types |
title_full_unstemmed | Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types |
title_short | Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types |
title_sort | metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types |
topic | ORIGINAL ARTICLES |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899631/ https://www.ncbi.nlm.nih.gov/pubmed/36156330 http://dx.doi.org/10.1111/cas.15602 |
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