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Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay

Obesity is associated with ~40% of cancer diagnoses but there are currently no effective preventive strategies, illustrating a need for chemoprevention. We previously demonstrated that fibroblast growth factor 2 (FGF2) from adipose tissue stimulates malignant transformation, as measured by growth in...

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Autores principales: Benham, Vanessa, Bullard, Blair, Dexheimer, Thomas S., Bernard, Matthew P., Neubig, Richard R., Liby, Karen T., Bernard, Jamie J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635484/
https://www.ncbi.nlm.nih.gov/pubmed/31311976
http://dx.doi.org/10.1038/s41598-019-46531-y
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author Benham, Vanessa
Bullard, Blair
Dexheimer, Thomas S.
Bernard, Matthew P.
Neubig, Richard R.
Liby, Karen T.
Bernard, Jamie J.
author_facet Benham, Vanessa
Bullard, Blair
Dexheimer, Thomas S.
Bernard, Matthew P.
Neubig, Richard R.
Liby, Karen T.
Bernard, Jamie J.
author_sort Benham, Vanessa
collection PubMed
description Obesity is associated with ~40% of cancer diagnoses but there are currently no effective preventive strategies, illustrating a need for chemoprevention. We previously demonstrated that fibroblast growth factor 2 (FGF2) from adipose tissue stimulates malignant transformation, as measured by growth in soft agar, the gold-standard in vitro transformation assay. Because the soft agar assay is unsuitable for high throughput screens (HTS), we developed a novel method using 3D growth in ultra-low attachment conditions as an alternative to growth in agar to discover compounds that inhibit transformation. Treating non-tumorigenic, skin epithelial JB6 P(+) cells with FGF2 stimulates growth in ultra-low attachment conditions analogous to growth in the soft agar. This transformation HTS identified picropodophyllin, an insulin growth factor 1 receptor (IGF1R) inhibitor, and fluvastatin, an HMG-CoA reductase inhibitor, as potential chemopreventive agents. These compounds were validated for efficacy using two non-tumorigenic cell lines in soft agar. Another IGF1R inhibitor and other statins were also tested and several were able to inhibit growth in soft agar. This novel 3D HTS platform is fast, robust and has the potential to identify agents for obesity-associated cancer prevention.
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spelling pubmed-66354842019-07-24 Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay Benham, Vanessa Bullard, Blair Dexheimer, Thomas S. Bernard, Matthew P. Neubig, Richard R. Liby, Karen T. Bernard, Jamie J. Sci Rep Article Obesity is associated with ~40% of cancer diagnoses but there are currently no effective preventive strategies, illustrating a need for chemoprevention. We previously demonstrated that fibroblast growth factor 2 (FGF2) from adipose tissue stimulates malignant transformation, as measured by growth in soft agar, the gold-standard in vitro transformation assay. Because the soft agar assay is unsuitable for high throughput screens (HTS), we developed a novel method using 3D growth in ultra-low attachment conditions as an alternative to growth in agar to discover compounds that inhibit transformation. Treating non-tumorigenic, skin epithelial JB6 P(+) cells with FGF2 stimulates growth in ultra-low attachment conditions analogous to growth in the soft agar. This transformation HTS identified picropodophyllin, an insulin growth factor 1 receptor (IGF1R) inhibitor, and fluvastatin, an HMG-CoA reductase inhibitor, as potential chemopreventive agents. These compounds were validated for efficacy using two non-tumorigenic cell lines in soft agar. Another IGF1R inhibitor and other statins were also tested and several were able to inhibit growth in soft agar. This novel 3D HTS platform is fast, robust and has the potential to identify agents for obesity-associated cancer prevention. Nature Publishing Group UK 2019-07-16 /pmc/articles/PMC6635484/ /pubmed/31311976 http://dx.doi.org/10.1038/s41598-019-46531-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Benham, Vanessa
Bullard, Blair
Dexheimer, Thomas S.
Bernard, Matthew P.
Neubig, Richard R.
Liby, Karen T.
Bernard, Jamie J.
Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay
title Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay
title_full Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay
title_fullStr Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay
title_full_unstemmed Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay
title_short Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay
title_sort identifying chemopreventive agents for obesity-associated cancers using an efficient, 3d high-throughput transformation assay
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635484/
https://www.ncbi.nlm.nih.gov/pubmed/31311976
http://dx.doi.org/10.1038/s41598-019-46531-y
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