TY - JOUR
T1 - Molecular and functional evaluation of a novel HIF inhibitor, benzopyranyl 1,2,3-triazole compound
AU - Park, Kyunghye
AU - Lee, Hye Eun
AU - Lee, Sun Hee
AU - Lee, Doohyun
AU - Lee, Taeho
AU - Lee, You Mie
PY - 2017
Y1 - 2017
N2 - Hypoxia occurs in a variety of pathological events, including the formation of solid tumors. Hypoxia-inducible factor (HIF)-1a is stabilized under hypoxic conditions and is a key molecule in tumor growth and angiogenesis. Seeking to develop novel cancer therapeutics, we investigated small molecules from our in-house chemical libraries to target HIF-1α. We employed a dual-luciferase assay that uses a luciferase (Luc) reporter vector harboring five copies of hypoxia-responsive element (HRE) in the promoter. Under hypoxic conditions that increased Luc reporter activity by fourfold, we screened 144 different compounds, nine of which showed 30-50% inhibition of hypoxia-induced Luc reporter activity. Among these, "Compound 12, a benzopyranyl 1,2,3-triazole" was the most efficient at inhibiting the expression of HIF-1α under hypoxic conditions, reducing its expression by 80%. Under hypoxic conditions, the half maximal IC50 of the compound was 24 nM in HEK-293 human embryonic kidney cells, and 2 nM in A549 human lung carcinoma cells. Under hypoxic conditions, Compound 12 increased hydroxylated HIF-1α levels and HIF-1α ubiquitination, and also dosedependently decreased HIF-1α target gene expression as well as vascular endothelial growth factor (VEGF) secretion. Furthermore, this compound inhibited VEGF-induced in vitro angiogenesis in human umbilical vein endothelial cells (HUVECs), and in vivo, it inhibited chick chorioallantoic membrane angiogenesis. In allogaft assays, cotreatment with Compound 12 and gefitinib significantly inhibited tumor growth and angiogenesis. Compound 12 can be a novel inhibitor of HIF-1α by accelerating its degradation, and shows much potential as an anti-cancer agent through its ability to suppress tumor growth and angiogenesis.
AB - Hypoxia occurs in a variety of pathological events, including the formation of solid tumors. Hypoxia-inducible factor (HIF)-1a is stabilized under hypoxic conditions and is a key molecule in tumor growth and angiogenesis. Seeking to develop novel cancer therapeutics, we investigated small molecules from our in-house chemical libraries to target HIF-1α. We employed a dual-luciferase assay that uses a luciferase (Luc) reporter vector harboring five copies of hypoxia-responsive element (HRE) in the promoter. Under hypoxic conditions that increased Luc reporter activity by fourfold, we screened 144 different compounds, nine of which showed 30-50% inhibition of hypoxia-induced Luc reporter activity. Among these, "Compound 12, a benzopyranyl 1,2,3-triazole" was the most efficient at inhibiting the expression of HIF-1α under hypoxic conditions, reducing its expression by 80%. Under hypoxic conditions, the half maximal IC50 of the compound was 24 nM in HEK-293 human embryonic kidney cells, and 2 nM in A549 human lung carcinoma cells. Under hypoxic conditions, Compound 12 increased hydroxylated HIF-1α levels and HIF-1α ubiquitination, and also dosedependently decreased HIF-1α target gene expression as well as vascular endothelial growth factor (VEGF) secretion. Furthermore, this compound inhibited VEGF-induced in vitro angiogenesis in human umbilical vein endothelial cells (HUVECs), and in vivo, it inhibited chick chorioallantoic membrane angiogenesis. In allogaft assays, cotreatment with Compound 12 and gefitinib significantly inhibited tumor growth and angiogenesis. Compound 12 can be a novel inhibitor of HIF-1α by accelerating its degradation, and shows much potential as an anti-cancer agent through its ability to suppress tumor growth and angiogenesis.
KW - Benzopyranyl 1,2,3-triazole
KW - Chemical library
KW - HIF-1α inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85018870705&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.13955
DO - 10.18632/oncotarget.13955
M3 - Article
C2 - 27999195
AN - SCOPUS:85018870705
SN - 1949-2553
VL - 8
SP - 7801
EP - 7813
JO - Oncotarget
JF - Oncotarget
IS - 5
ER -