title: The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway.
abstract: Despite its importance, the death rate of ovarian cancer has remained unchanged over the past five decades, demanding an improvement in prevention and treatment of this malignancy. With no known carcinogens, targeted prevention is currently unavailable, and efforts in early detection of this malignancy by screening biomarkers have failed. The inhibition of angiogenesis, also known as angioprevention, is a promising strategy to limit the growth of solid tumors, including ovarian cancers. Nobiletin, a polymethoxy flavonoid compound isolated from the tiansheng plant, has been shown to inhibit the growth of multiple types of human cancers. However, there are no reports involving the effect on nobiletin on human ovarian cancer. The present report shows that nobiletin potently decreases the viability of ovarian cancer cells in vitro. However, nobiletin does not affect the viability of normal ovarian epithelial cells at <40 µM. The antitumor activity of nobiletin was also observed in athymic mouse models and in chicken chorioallantoic membrane (CAM) models. The anti-neoplastic activity of nobiletin was due to its ability to inhibit angiogenesis. We also studied the molecular mechanisms by which nobiletin suppresses angiogenesis. We observed that nobiletin inhibits secretion of the key angiogenesis mediators, Akt, HIF-1α, NF-κB and vascular epithelial growth factor (VEGF) by ovarian cancer cells. Transient transfection experiments showed that nobiletin inhibits production of HIF-1α by downregulation of Akt. Such decreased levels of HIF-1α were responsible for nobiletin-induced suppression of VEGF. Our data suggest that nobiletin may be a promising anti-angiogenic agent relevant for therapy of ovarian cancers.
authors.affiliation: College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, P.R. China.
authors.forename: Jianchu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Science, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Allen Y
authors.initials: AY
authors.lastname: Chen
authors.affiliation: College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, P.R. China.
authors.forename: Haizhi
authors.initials: H
authors.lastname: Huang
authors.affiliation: College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, P.R. China.
authors.forename: Xingqian
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Rollyson
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Perry
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Brown
authors.affiliation: Department of Pharmaceutical Science, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Gary O
authors.initials: GO
authors.lastname: Rankin
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Piyali
authors.initials: P
authors.lastname: Dasgupta
authors.affiliation: College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA.
authors.forename: Yi Charlie
authors.initials: YC
authors.lastname: Chen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000187:drug effects*; D005260:Female; D047309:Flavones / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D047309:Flavones; C008661:nobiletin; D051057:Proto-Oncogene Proteins c-akt
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