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Mar. Drugs 2018, 16(7), 241; https://doi.org/10.3390/md16070241

Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models

1
Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
2
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 5JJ, UK
3
School of Chemical Sciences, University of Auckland, Auckland 1142, New Zealand
4
Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
*
Author to whom correspondence should be addressed.
Received: 20 June 2018 / Revised: 9 July 2018 / Accepted: 16 July 2018 / Published: 19 July 2018
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Abstract

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. View Full-Text
Keywords: discorhabdins; hypoxia; HIF; angiogenesis; marine natural products; alkaloids discorhabdins; hypoxia; HIF; angiogenesis; marine natural products; alkaloids
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Harris, E.M.; Strope, J.D.; Beedie, S.L.; Huang, P.A.; Goey, A.K.L.; Cook, K.M.; Schofield, C.J.; Chau, C.H.; Cadelis, M.M.; Copp, B.R.; Gustafson, K.R.; Figg, W.D. Preclinical Evaluation of Discorhabdins in Antiangiogenic and Antitumor Models. Mar. Drugs 2018, 16, 241.

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