NNC 55-0396, a T-type Ca^sup 2+^ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1[alpha] signal transduction

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 93; no. 5; p. 499
• Main Authors: Kim, Ki Hyun, Kim, Dongyoung, Park, Ju Yeol, Jung, Hye Jin, Cho, Yong-hee, Kim, Hyoung Kyu, Han, Jin, Choi, Kang-yell, Kwon, Ho Jeong
• Format: Journal Article
• Language: English
• Published: New York Springer Nature B.V 01.05.2015
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-014-1235-1

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