A novel Ca2+/calmodulin antagonist HBC inhibits angiogenesis and down-regulates hypoxia-inducible factor

Hye Jin Jung, Jong Hyeon Kim, Joong Sup Shim, Ho Jeong Kwon

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Recent reports have shown that Ca2+/calmodulin (Ca2+/ CaM) signaling plays a crucial role in angiogenesis. We previously developed a new Ca2+/CaM antagonist, HBC (4-{3,5-bis-[2-(4-hydroxy-3- methoxyphenyl)ethyl]-4,5-dihydropyrazol-1-yl}benzoic acid), from a curcumin-based synthetic chemical library. Here, we investigated its anti-angiogenic activity and mode of action. HBC potently inhibited the proliferation of human umbilical vascular endothelial cells with no cytotoxicity. Furthermore, HBC blocked in vitro characteristics of angiogenesis such as tube formation and chemoinvasion, as well as neovascularization of the chorioallantoic membrane of growing chick embryos in vivo. Notably,HBCmarkedly inhibited expression of hypoxia-inducible factor-1α (HIF-1α) at the translational level during hypoxia, thereby reducing HIF-1 transcriptional activity and expression of its major target gene, vascular endothelial growth factor. In addition, combination treatment with HBC and various HIF-1 inhibitors, including suberoylanilide hydroxamic acid, rapamycin, and terpestacin, had greater anti-angiogenic activity than treatment with each single agent. Collectively, our findings indicate that HBC is a new anti-angiogenic agent targeting HIF that can be used to explore the biological role of Ca2+/CaM in angiogenesis.

Original languageEnglish
Pages (from-to)25867-25874
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number33
DOIs
Publication statusPublished - 2010 Aug 13

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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