title: 6-(1-Oxobutyl)-5,8-dimethoxy-1,4-naphthoquinone inhibits lewis lung cancer by antiangiogenesis and apoptosis.
abstract: Lung cancer is a leading cause of cancer mortality worldwide. Novel and nontoxic agents targeting angiogenesis and tumor cell proliferation and survival are desirable for lung cancer chemoprevention and treatment. Previously we have reported that 6-(1-oxobutyl)-5,8-dimethoxy-1,4-naphthoquinone (OXO) exhibits anti-tumor activity against S-180 sarcoma in vitro and in vivo. Here we studied the anti-angiogenic and apoptogenic attributes of OXO in vitro and in vivo targeting lung cancer. In human umbilical vein endothelial cells (HUVECs), we show that OXO more potently inhibited VEGF-stimulated than basic bFGF-stimulated HUVEC proliferation and capillary differentiation. In Lewis lung carcinoma (LLC) cells, OXO not only induces S-phase arrest and mitochondria/caspase-9 pathway mediated apoptosis, but also effectively down-regulated the hypoxia-induced expression of HIF-1alpha and VEGF at mRNA and protein levels in LLC and decreased VEGF secretion into conditioned culture media. OXO significantly reduced in vivo functional angiogenesis in the mouse Matrigel plug assay. Furthermore, OXO potently inhibited the growth of LLC cells inoculated on the flank of syngenic mice at dosages that did not affect their body weight. The in vivo anti-cancer effect was associated with decreased HIF-1alpha and VEGF expression, decreased microvessel density as well as a reduction of tumor cell proliferation and increased tumor cell apoptosis. Taken together, these results demonstrate that OXO exerts anti-cancer activity through anti-angiogenesis and tumor cell cycle arrest and apoptosis. These findings warrant additional studies of OXO as a novel agent for the chemoprevention and treatment of lung cancer.
authors.affiliation: Laboratory of Angiogenesis and Chemoprevention, College of Oriental Medicine, Kyunghee University, Seoul, South Korea.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Gyu-Yong
authors.initials: GY
authors.lastname: Song
authors.forename: Guangxun
authors.initials: G
authors.lastname: Li
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lü
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009285:Naphthoquinones / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: C520370:6-(1-oxobutyl)-5,8-dimethoxy-1,4-naphthoquinone; D020533:Angiogenesis Inhibitors; D009285:Naphthoquinones; D042461:Vascular Endothelial Growth Factor A