Cargando…
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...
Autores principales: | , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783343796843446272 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6071056 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT harrisemilym preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT stropejonathand preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT beedieshaunnal preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT huangphoebea preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT goeyandrewkl preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT cookkristinam preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT schofieldchristopherj preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT chaucindyh preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT cadelismelissam preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT coppbrentr preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT gustafsonkirkr preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels AT figgwilliamd preclinicalevaluationofdiscorhabdinsinantiangiogenicandantitumormodels |