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 language | English |
|---|---|
| Pages (from-to) | 499-509 |
| Number of pages | 11 |
| Journal | Journal of Molecular Medicine |
| Volume | 93 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2015 May 1 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery
- Genetics(clinical)
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NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction. / 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.
In: Journal of Molecular Medicine, Vol. 93, No. 5, 01.05.2015, p. 499-509.Research output: Contribution to journal › Article
TY - JOUR
T1 - NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction
AU - Kim, Ki Hyun
AU - Kim, Dongyoung
AU - Park, Ju Yeol
AU - Jung, Hye Jin
AU - Cho, Yong Hee
AU - Kim, Hyoung Kyu
AU - Han, Jin
AU - Choi, Kang-Yell
AU - Kwon, Ho Jeong
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s00109-014-1235-1
DO - 10.1007/s00109-014-1235-1
M3 - Article
VL - 93
SP - 499
EP - 509
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
IS - 5
ER -