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Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models

Elements of the hypoxia inducible factor (HIF) transcriptional system, a key regulator of the cellular hypoxic response, are up-regulated in a range of cancer cells. HIF is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of the transcriptional activity of HI...

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Autores principales: Harris, Emily M., Strope, Jonathan D., Beedie, Shaunna L., Huang, Phoebe A., Goey, Andrew K. L., Cook, Kristina M., Schofield, Christopher J., Chau, Cindy H., Cadelis, Melissa M., Copp, Brent R., Gustafson, Kirk R., Figg, William D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071056/
https://www.ncbi.nlm.nih.gov/pubmed/30029505
http://dx.doi.org/10.3390/md16070241
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author Harris, Emily M.
Strope, Jonathan D.
Beedie, Shaunna L.
Huang, Phoebe A.
Goey, Andrew K. L.
Cook, Kristina M.
Schofield, Christopher J.
Chau, Cindy H.
Cadelis, Melissa M.
Copp, Brent R.
Gustafson, Kirk R.
Figg, William D.
author_facet Harris, Emily M.
Strope, Jonathan D.
Beedie, Shaunna L.
Huang, Phoebe A.
Goey, Andrew K. L.
Cook, Kristina M.
Schofield, Christopher J.
Chau, Cindy H.
Cadelis, Melissa M.
Copp, Brent R.
Gustafson, Kirk R.
Figg, William D.
author_sort Harris, Emily M.
collection PubMed
description Elements of the hypoxia inducible factor (HIF) transcriptional system, a key regulator of the cellular hypoxic response, are up-regulated in a range of cancer cells. HIF is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of the transcriptional activity of HIF may be of therapeutic benefit to cancer patients. We recently described the identification of two marine pyrroloiminoquinone alkaloids with potent activity in inhibiting the interaction between the oncogenic transcription factor HIF-1α and the coactivator protein p300. Herein, we present further characterization data for these two screening hits: discorhabdin H (1) and discorhabdin L (2), with a specific focus on their anti-angiogenic and anti-tumor effects. We demonstrated that only discorhabdin L (2) possesses excellent anti-angiogenic activity in inhibiting endothelial cell proliferation and tube formation, as well as decreasing microvessel outgrowth in the ex vivo rat aortic ring assay. We further showed that discorhabdin L (2) significantly inhibits in vivo prostate tumor growth in a LNCaP xenograft model. In conclusion, our findings suggest that discorhabdin L (2) represents a promising HIF-1α inhibitor worthy of further drug development.
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spelling pubmed-60710562018-08-09 Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models Harris, Emily M. Strope, Jonathan D. Beedie, Shaunna L. Huang, Phoebe A. Goey, Andrew K. L. Cook, Kristina M. Schofield, Christopher J. Chau, Cindy H. Cadelis, Melissa M. Copp, Brent R. Gustafson, Kirk R. Figg, William D. Mar Drugs Article Elements of the hypoxia inducible factor (HIF) transcriptional system, a key regulator of the cellular hypoxic response, are up-regulated in a range of cancer cells. HIF is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of the transcriptional activity of HIF may be of therapeutic benefit to cancer patients. We recently described the identification of two marine pyrroloiminoquinone alkaloids with potent activity in inhibiting the interaction between the oncogenic transcription factor HIF-1α and the coactivator protein p300. Herein, we present further characterization data for these two screening hits: discorhabdin H (1) and discorhabdin L (2), with a specific focus on their anti-angiogenic and anti-tumor effects. We demonstrated that only discorhabdin L (2) possesses excellent anti-angiogenic activity in inhibiting endothelial cell proliferation and tube formation, as well as decreasing microvessel outgrowth in the ex vivo rat aortic ring assay. We further showed that discorhabdin L (2) significantly inhibits in vivo prostate tumor growth in a LNCaP xenograft model. In conclusion, our findings suggest that discorhabdin L (2) represents a promising HIF-1α inhibitor worthy of further drug development. MDPI 2018-07-19 /pmc/articles/PMC6071056/ /pubmed/30029505 http://dx.doi.org/10.3390/md16070241 Text en © 2018 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
Harris, Emily M.
Strope, Jonathan D.
Beedie, Shaunna L.
Huang, Phoebe A.
Goey, Andrew K. L.
Cook, Kristina M.
Schofield, Christopher J.
Chau, Cindy H.
Cadelis, Melissa M.
Copp, Brent R.
Gustafson, Kirk R.
Figg, William D.
Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models
title Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models
title_full Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models
title_fullStr Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models
title_full_unstemmed Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models
title_short Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models
title_sort preclinical evaluation of discorhabdins in antiangiogenic and antitumor models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071056/
https://www.ncbi.nlm.nih.gov/pubmed/30029505
http://dx.doi.org/10.3390/md16070241
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