title: Anticancer imidazoacridinone C-1311 inhibits hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and angiogenesis.
abstract: 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 down-regulation 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 days) 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 days), 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.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, Gdańsk, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Paradziej-Łukowicz
authors.forename: Anna
authors.initials: A
authors.lastname: Skwarska
authors.forename: Grażyna
authors.initials: G
authors.lastname: Peszyńska-Sularz
authors.forename: Anna
authors.initials: A
authors.lastname: Brillowska-Dąbrowska
authors.forename: Jerzy
authors.initials: J
authors.lastname: Konopa
mesh_terms: D000609:Aminoacridines / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002474:Cell-Free System; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D020218:Response Elements; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000609:Aminoacridines; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; C098965:C 1311