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

Abstract

UNLABELLED:

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.

KEY MESSAGE:

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: 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
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 93 Issue 5 Pg. 499-509 (May 2015) ISSN: 1432-1440 [Electronic] Germany
• PMID: 25471482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Benzimidazoles
• Calcium Channel Blockers
• Calcium Channels, T-Type
• Cyclopropanes
• Hypoxia-Inducible Factor 1, alpha Subunit
• Naphthalenes
• NNC 55-0396
• Proteasome Endopeptidase Complex

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Benzimidazoles (pharmacology)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, T-Type (genetics, metabolism)
• Cell Line
• Cyclopropanes (pharmacology)
• Disease Models, Animal
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Mitochondria (drug effects, metabolism)
• Naphthalenes (pharmacology)
• Neoplasms (drug therapy, genetics, metabolism, pathology)
• Neovascularization, Pathologic (drug therapy, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Biosynthesis (drug effects)
• Protein Stability (drug effects)
• Proteolysis (drug effects)
• Signal Transduction (drug effects)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays