title: Angiostatic actions of capsicodendrin through selective inhibition of VEGFR2-mediated AKT signaling and disregulated autophagy.
abstract: Angiogenesis is the formation of new blood vessels from existing vasculature critical for embryonic development and vascular remodeling. Its dysregulation underlies numerous pathologic states ranging from ischemia to tumor growth and as such identifying new targeted- therapies is of significant interest for angiogenesis-based medicine. Here we evaluated the potential angiostatic properties of capsicodendrin (CPCD), a natural compound isolated from Cinnamosma macrocarpa, a plant belonging to the Malagasy Cinnamosma. CPCD potently inhibits endothelial proliferation, migration and capillary tube formation at nanomolar to low micromolar concentrations without inducing cytotoxic effects. We show that CPCD directly inactivates VEGFR2 and downstream AKT signaling, thereby strongly inducing autophagy as determined by increased expression of beclin1, autophagy-related gene (Atg) 3, Atg5 and LC3 cleavage. Ectopic AKT overexpression counteracts the inhibitory effects of CPCD on proliferation and capillary tubule formation. Importantly, CPCD treatment in vivo inhibits sprouting angiogenesis as evidenced by strongly reduced intersegmental vessel (ISV) sprouting and subintestinal vessel (SIV) formation during zebrafish embryonic development, and correlates with increased presence of LC3II along the ISVs despite overall reduced vasculature. These findings demonstrate CPCD as a potent inhibitor of the VEGFR2/AKT pathway at nanomolar concentrations and inducer of autophagy-related angiostatic effects.
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, OH, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Pan
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, OH, USA.
authors.forename: Nirav
authors.initials: N
authors.lastname: Shah
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, OH, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, OH, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wheeler
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, OH, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Cinti
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, OH, USA.
authors.forename: Dale G
authors.initials: DG
authors.lastname: Hoyt
authors.affiliation: Department of Neuroscience, The Ohio State University, OH, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Beattie
authors.affiliation: Department of Neuroscience, The Ohio State University, OH, USA.
authors.forename: Min
authors.initials: M
authors.lastname: An
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Mythreye
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, OH, USA.
authors.forename: L Harinantenaina
authors.initials: LH
authors.lastname: Rakotondraibe
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, OH, USA.|Davis Heart Lung Research Institute, The Ohio State University, OH, USA.|Comprehensive Cancer Center, The Ohio State University, OH, USA.
authors.forename: Nam Y
authors.initials: NY
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D029562:Magnoliaceae; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D010936:Plant Extracts; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; VEGF; angiogenesis; autophagy; endothelium