title: Suppression of hypoxia-induced HIF-1alpha accumulation by VEGFR inhibitors: Different profiles of AAL993 versus SU5416 and KRN633.
abstract: The hypoxia-inducible factor (HIF) is a heterodimeric basic helix-loop-helix transcriptional factor and the activated HIF plays pivotal roles in various pathological conditions, including inflammation and cancer. HIF-1alpha overexpression has been observed in many common human cancers, including brain, breast, colon, lung, ovary, and prostate, and HIF-mediated genes, such as vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), and insulin-like growth factor (IGF)-1, are associated with tumor angiogenesis, metastasis, and invasion. Therefore, the pro-oncogenic protein HIF is a novel target of cancer therapy. We examined the effects of VEGFR inhibitors, AAL993, SU5416, and KRN633, on suppression of HIF-1alpha accumulation under the hypoxic condition. We found that VEGFR tyrosine kinase inhibitors, AAL993, SU5416, and KRN633, possess dual functions: inhibition of VEGFR signaling and HIF-1alpha expression under the hypoxic condition. The detailed mechanistic study indicated that SU5416 and KRN633 suppressed HIF-1alpha expression through inhibition of both Akt and ERK phosphorylation signaling pathways, whereas AAL993 suppressed HIF-1alpha expression through ERK inhibition without affecting Akt phosphorylation.
authors.affiliation: Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Tokyo 171-8588, Japan.
authors.forename: Hyun Seung
authors.initials: HS
authors.lastname: Ban
authors.forename: Masaharu
authors.initials: M
authors.lastname: Uno
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms; D017931:DNA Primers; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D017931:DNA Primers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D010671:Phenylurea Compounds; D011758:Pyrroles; D011799:Quinazolines; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; C508488:N-(2-chloro-4-((6,7-dimethoxy-4-quinazolinyl)oxy)phenyl)-N'-propylurea; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D040262:Receptors, Vascular Endothelial Growth Factor; D004259:DNA-Directed DNA Polymerase