title: NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction.
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 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-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 Ca(2+) 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.
  
  
  CONCLUSIONS
  HIF-1α overexpression has been demonstrated in hypoxic cancer cells. NNC 55-0396, a T-type Ca(2+) channel inhibitor, inhibited HIF-1α expression via both proteasomal degradation and protein synthesis pathways. T-type Ca(2+) channel inhibitors block angiogenesis by suppressing HIF-1α stability and synthesis. NNC 55-0396 could be a potential therapeutic drug candidate for cancer treatment.
authors.affiliation: Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, South Korea.
authors.forename: Ki Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Dongyoung
authors.initials: D
authors.lastname: Kim
authors.forename: Ju Yeol
authors.initials: JY
authors.lastname: Park
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Cho
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003521:Cyclopropanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D003521:Cyclopropanes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009281:Naphthalenes; C484287:NNC 55-0396; D046988:Proteasome Endopeptidase Complex