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

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 languageEnglish
Pages (from-to)499-509
Number of pages11
JournalJournal of Molecular Medicine
Volume93
Issue number5
DOIs
Publication statusPublished - 2015 May 1

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Hypoxia-Inducible Factor 1
Angiogenesis Inhibitors
Signal Transduction
Neoplasms
(1S,2S)-2-(2-(N-((3-benzimidazol-2-yl)propyl)-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride
Protein Stability
Protein Transport
Glioblastoma
Growth
Galactose
Ion Channels
Heterografts
Proteolysis
Reactive Oxygen Species
Cell Survival
Respiration
Cell Proliferation
Glucose

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

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. / NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction. In: Journal of Molecular Medicine. 2015 ; Vol. 93, No. 5. pp. 499-509.
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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.",
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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 journalArticle

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

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SP - 499

EP - 509

JO - Journal of Molecular Medicine

JF - Journal of Molecular Medicine

SN - 0946-2716

IS - 5

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