Angiostatic actions of capsicodendrin through selective inhibition of VEGFR2-mediated AKT signaling and disregulated autophagy

Christopher C. Pan, Nirav Shah, Sanjay Kumar, Sarah E. Wheeler, Jason Cinti, Dale G. Hoyt, Christine E. Beattie, Min An, Karthikeyan Mythreye, L. Harinantenaina Rakotondraibe, Nam Y. Lee

Research output: Contribution to journalArticle

7 Scopus citations

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 angiogenesisbased 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.

Original languageEnglish (US)
Pages (from-to)12675-12685
Number of pages11
JournalOncotarget
Volume8
Issue number8
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • AKT
  • Angiogenesis
  • Autophagy
  • Endothelium
  • VEGF

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Pan, C. C., Shah, N., Kumar, S., Wheeler, S. E., Cinti, J., Hoyt, D. G., Beattie, C. E., An, M., Mythreye, K., Rakotondraibe, L. H., & Lee, N. Y. (2017). Angiostatic actions of capsicodendrin through selective inhibition of VEGFR2-mediated AKT signaling and disregulated autophagy. Oncotarget, 8(8), 12675-12685. https://doi.org/10.18632/oncotarget.9307