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

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Kim KH, Kim D, Park JY, Jung HJ, Cho YH, Kim HK, Han J, Choi KY, Kwon HJ

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

J Mol Med (Berl). 2015 May;93(5):499-509. doi: 10.1007/s00109-014-1235-1. Epub 2014 Dec 4.

PubMed ID
25471482 [ View in PubMed
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Abstract

UNLABELLED: Mitochondrial respiration is required for hypoxia-inducible factor (HIF)-1alpha stabilization, which is important for tumor cell survival, proliferation, and angiogenesis. Herein, small molecules that inhibit HIF-1alpha 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 Ca(2+) channel inhibitor, was selected as a hit from among 1,280 small molecules. NNC 55-0396 suppressed mitochondrial reactive oxygen species-mediated HIF-1alpha 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-1alpha stability. Moreover, NNC 55-0396 significantly suppressed glioblastoma tumor growth in a xenograft model. Thus, NNC 55-0396, a small molecule targeting T-type Ca(2+) channel, was identified by the systemic cell-based assay and was shown to have antiangiogenic activity via the suppression of HIF-1alpha signal transduction. These results provide new insights into the biological network between ion channel and HIF-1alpha signal transduction. KEY MESSAGE: HIF-1alpha overexpression has been demonstrated in hypoxic cancer cells. NNC 55-0396, a T-type Ca(2+) channel inhibitor, inhibited HIF-1alpha expression via both proteasomal degradation and protein synthesis pathways. T-type Ca(2+) channel inhibitors block angiogenesis by suppressing HIF-1alpha stability and synthesis. NNC 55-0396 could be a potential therapeutic drug candidate for cancer treatment.

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