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Title: OSU-A9 inhibits angiogenesis in human umbilical vein endothelial cells via disrupting Akt–NF-κB and MAPK signaling pathways

Since the introduction of angiogenesis as a useful target for cancer therapy, few agents have been approved for clinical use due to the rapid development of resistance. This problem can be minimized by simultaneous targeting of multiple angiogenesis signaling pathways, a potential strategy in cancer management known as polypharmacology. The current study aimed at exploring the anti-angiogenic activity of OSU-A9, an indole-3-carbinol-derived pleotropic agent that targets mainly Akt–nuclear factor-kappa B (NF-κB) signaling which regulates many key players of angiogenesis such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Human umbilical vein endothelial cells (HUVECs) were used to study the in vitro anti-angiogenic effect of OSU-A9 on several key steps of angiogenesis. Results showed that OSU-A9 effectively inhibited cell proliferation and induced apoptosis and cell cycle arrest in HUVECs. Besides, OSU-A9 inhibited angiogenesis as evidenced by abrogation of migration/invasion and Matrigel tube formation in HUVECs and attenuation of the in vivo neovascularization in the chicken chorioallantoic membrane assay. Mechanistically, Western blot, RT-PCR and ELISA analyses showed the ability of OSU-A9 to inhibit MMP-2 production and VEGF expression induced by hypoxia or phorbol-12-myristyl-13-acetate. Furthermore, dual inhibition of Akt–NF-κB and mitogen-activated protein kinase (MAPK) signaling, the key regulators of angiogenesis, wasmore » observed. Together, the current study highlights evidences for the promising anti-angiogenic activity of OSU-A9, at least in part through the inhibition of Akt–NF-κB and MAPK signaling and their consequent inhibition of VEGF and MMP-2. These findings support OSU-A9's clinical promise as a component of anticancer therapy. - Highlights: • The antiangiogenic activity of OSU-A9 in HUVECs was explored. • OSU-A9 inhibited HUVECs proliferation, migration, invasion and tube formation. • OSU-A9 targeted signaling pathways mediated by Akt-NF-kB, VEGF, and MMP-2. • The anti-angiogenic activity of OSU-A9 supports its clinical promise.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7]
  1. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210 (United States)
  2. (Egypt)
  3. Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514 (Egypt)
  4. Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11511 (Egypt)
  5. Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562 (Egypt)
  6. School of Pharmacy, China Medical University, Taichung 40402, Taiwan (China)
  7. Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan (China)
Publication Date:
OSTI Identifier:
22285454
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 272; Journal Issue: 3; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETATES; ADP; ANGIOGENESIS; CELL PROLIFERATION; DMSO; FETAL MEMBRANES; GROWTH FACTORS; NEOPLASMS; PHOSPHOTRANSFERASES; RETINOIC ACID; RIBOSE; SIGNALS; TETRAZOLIUM; THERAPY; VEINS