NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction

Ki Hyun Kim, Dongyoung Kim, Ju Yeol Park, Hye Jin Jung, Yong Hee Cho, Hyoung Kyu Kim, Jin Han, Kang-Yell Choi, Ho Jeong Kwon

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17 Citations (Scopus)

Abstract

Abstract: Mitochondrial respiration is required for hypoxia-inducible factor (HIF)-1α stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Herein, small molecules that inhibit HIF-1α protein stability by targeting mitochondrial energy production were screened using the Library of Pharmacologically Active Compounds and cell growth assay in galactose or glucose medium. NNC 55-0396, a T-type Ca2+ channel inhibitor, was selected as a hit from among 1,280 small molecules. NNC 55-0396 suppressed mitochondrial reactive oxygen species-mediated HIF-1α expression as well as stabilization by inhibiting protein synthesis in a dose-dependent manner. NNC 55-0396 inhibited tumor-induced angiogenesis in vitro and in vivo by suppressing HIF-1α stability. Moreover, NNC 55-0396 significantly suppressed glioblastoma tumor growth in a xenograft model. Thus, NNC 55-0396, a small molecule targeting T-type Ca2+ channel, was identified by the systemic cell-based assay and was shown to have antiangiogenic activity via the suppression of HIF-1α signal transduction. These results provide new insights into the biological network between ion channel and HIF-1α signal transduction. Key message: HIF-1α overexpression has been demonstrated in hypoxic cancer cells.NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibited HIF-1α expression via both proteasomal degradation and protein synthesis pathways.T-type Ca2+ channel inhibitors block angiogenesis by suppressing HIF-1α stability and synthesis.NNC 55-0396 could be a potential therapeutic drug candidate for cancer treatment.

Original languageEnglish
Pages (from-to)499-509
Number of pages11
JournalJournal of Molecular Medicine
Volume93
Issue number5
DOIs
Publication statusPublished - 2015 May 1

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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