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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.
AuthorsJianchu Chen, Allen Y Chen, Haizhi Huang, Xingqian Ye, William D Rollyson, Haley E Perry, Kathleen C Brown, Yon Rojanasakul, Gary O Rankin, Piyali Dasgupta, Yi Charlie Chen
JournalInternational journal of oncology (Int J Oncol) Vol. 46 Issue 6 Pg. 2629-38 ( 2015) ISSN: 1791-2423 [Electronic] Greece
PMID25845666 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiogenesis Inhibitors
  • Antineoplastic Agents, Phytogenic
  • Flavones
  • nobiletin
  • Proto-Oncogene Proteins c-akt
Topics
  • Angiogenesis Inhibitors (administration & dosage, pharmacology)
  • Animals
  • Antineoplastic Agents, Phytogenic (administration & dosage, pharmacology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Chick Embryo
  • Chorioallantoic Membrane (drug effects)
  • Female
  • Flavones (administration & dosage, pharmacology)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Male
  • Mice
  • Ovarian Neoplasms (drug therapy, metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Signal Transduction (drug effects)
  • Xenograft Model Antitumor Assays

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