Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models
Emily M. Harris,
Jonathan D. Strope,
Shaunna L. Beedie,
Phoebe A. Huang,
Andrew K. L. Goey,
Kristina M. Cook,
Christopher J. Schofield,
Cindy H. Chau,
Melissa M. Cadelis,
Brent R. Copp,
Kirk R. Gustafson,
William D. Figg
Affiliations
Emily M. Harris
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Jonathan D. Strope
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Shaunna L. Beedie
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Phoebe A. Huang
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Andrew K. L. Goey
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Kristina M. Cook
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Christopher J. Schofield
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 5JJ, UK
Cindy H. Chau
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Melissa M. Cadelis
School of Chemical Sciences, University of Auckland, Auckland 1142, New Zealand
Brent R. Copp
School of Chemical Sciences, University of Auckland, Auckland 1142, New Zealand
Kirk R. Gustafson
Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
William D. Figg
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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.
