TY - JOUR
T1 - Anticancer imidazoacridinone C-1311 inhibits hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and angiogenesis
AU - Paradziej-Łukowicz, Jolanta
AU - Skwarska, Anna
AU - Peszyńska-Sularz, Grazyna
AU - Brillowska-Da̧browska, Anna
AU - Konopa, Jerzy
PY - 2011/10/1
Y1 - 2011/10/1
N2 - Antitumor imidazoacridinone C-1311 is a DNA-reactive topoisomerase II and FLT3 receptor tyrosine kinase inhibitor. Here, we demonstrate the mechanism of C-1311 inhibitory action on novel targets: hypoxia-inducible factor-1α (HIF-1α), vascular-endothelial growth factor (VEGF), and angiogenesis. In a cell-free system, C-1311 prevented HIF-1α binding to an oligonucleotide encompassing a canonical hypoxia-responsive element (HRE), but did not directly interfere with HIF-1α protein. Whereas C-1311 did not affect HIF-1α transcription, at higher concentrations (10 μM), it decreased HIF-1α protein accumulation. Furthermore, C-1311 potently reduced the transcription of HIF-1-dependent reporter gene as well as endogenous HIF-1 target gene encoding vascular endothelial growth factor. In colon cancer HCT116 and murine melanoma B16/F10 cells, C-1311-induced downregulation of VEGF, resulted in decreased VEGF protein expression. C-1311 did not alter normoxic VEGF secretion. Consistent with VEGF depletion, C-1311 significantly affected angiogenesis in vivo. A single dose of C-1311 (40 mg/kg), inhibited angiogenesis by 70%, as measured by vascularization of Matrigel plugs in mice. Continuous low C-1311 dosing (8 mg/kg/day for 5 d) gave similar inhibition of angiogenesis (80%), suggesting that low-dose, frequent C-1311 administration may be more effective in terms of reducing toxicity. Anti-angiogenic activity of C-1311 was further demonstrated in an experimental model in which B16/F10 cells were encapsulated in alginate beads and implanted into mice. C-1311 (8 mg/kg/day for 9 d), completely abrogated vascularization of the alginate implants. Our findings indicate that C-1311 is an effective inhibitor of HIF-1α, VEGF and angiogenesis and provide new perspectives into the mechanism of its anticancer activity.
AB - Antitumor imidazoacridinone C-1311 is a DNA-reactive topoisomerase II and FLT3 receptor tyrosine kinase inhibitor. Here, we demonstrate the mechanism of C-1311 inhibitory action on novel targets: hypoxia-inducible factor-1α (HIF-1α), vascular-endothelial growth factor (VEGF), and angiogenesis. In a cell-free system, C-1311 prevented HIF-1α binding to an oligonucleotide encompassing a canonical hypoxia-responsive element (HRE), but did not directly interfere with HIF-1α protein. Whereas C-1311 did not affect HIF-1α transcription, at higher concentrations (10 μM), it decreased HIF-1α protein accumulation. Furthermore, C-1311 potently reduced the transcription of HIF-1-dependent reporter gene as well as endogenous HIF-1 target gene encoding vascular endothelial growth factor. In colon cancer HCT116 and murine melanoma B16/F10 cells, C-1311-induced downregulation of VEGF, resulted in decreased VEGF protein expression. C-1311 did not alter normoxic VEGF secretion. Consistent with VEGF depletion, C-1311 significantly affected angiogenesis in vivo. A single dose of C-1311 (40 mg/kg), inhibited angiogenesis by 70%, as measured by vascularization of Matrigel plugs in mice. Continuous low C-1311 dosing (8 mg/kg/day for 5 d) gave similar inhibition of angiogenesis (80%), suggesting that low-dose, frequent C-1311 administration may be more effective in terms of reducing toxicity. Anti-angiogenic activity of C-1311 was further demonstrated in an experimental model in which B16/F10 cells were encapsulated in alginate beads and implanted into mice. C-1311 (8 mg/kg/day for 9 d), completely abrogated vascularization of the alginate implants. Our findings indicate that C-1311 is an effective inhibitor of HIF-1α, VEGF and angiogenesis and provide new perspectives into the mechanism of its anticancer activity.
KW - Angiogenesis
KW - Chemotherapy
KW - HIF-1
KW - Hypoxia
KW - Imidazoacridinone C-1311
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=80052898350&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052898350&partnerID=8YFLogxK
U2 - 10.4161/cbt.12.7.15980
DO - 10.4161/cbt.12.7.15980
M3 - Article
C2 - 21775820
AN - SCOPUS:80052898350
SN - 1538-4047
VL - 12
SP - 586
EP - 597
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 7
ER -