title: Epoxyquinol B shows antiangiogenic and antitumor effects by inhibiting VEGFR2, EGFR, FGFR, and PDGFR.
abstract: Angiogenesis is the development of new blood vessels to provide oxygen and nutrients and is indispensable for solid tumor growth. Therefore, the inhibition of angiogenesis is an important modality for cancer chemotherapy. Here we report the antiangiogenic mechanism and antitumor effects of epoxyquinol B (EPQB), which was isolated from fungal metabolites. Short-term treatment of EPQB resulted in the reduction of tumor growth and the number of blood vessels directed to the tumor in a murine xenografts model. Furthermore, EPQB inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation in human umbilical vein endothelial cells (HUVECs) without cytotoxicity. VEGF-stimulated phosphorylation of VEGF receptor 2 (VEGFR2), phospholipase Cgamma-1 (PLCgamma1), and p44/42 MAP kinases (ERK) was inhibited by EPQB in a dose-dependent manner, and in vitro assay using kinase domain of VEGFR2 showed that EPQB covalently bound and inhibited the VEGFR2 kinase. Its binding site on VEGFR2 was different from SU5614, a well-known VEGFR2 kinase inhibitor. Interestingly, EPQB inhibited growth factor-induced activation of not only VEGFR2 but also epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR), suggesting that EPQB is a novel multiple kinase inhibitor. These findings suggest that EPQB would be a good lead compound for the development of potent antiangiogenic and antitumor drugs.
authors.affiliation: Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kamiyama
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kakeya
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shoji
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004852:Epoxy Compounds / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D006873:Hydroquinones; D017468:Receptors, Fibroblast Growth Factor; C469247:epoxyquinol B; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2