The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway

Chen,Jianchu; Chen,Allen Y.; Huang,Haizhi; Ye,Xingqian; Rollyson,William D.; Perry,Haley E.; Brown,Kathleen C.; Rojanasakul,Yon; Rankin,Gary O.; Dasgupta,Piyali; Chen,Yi Charlie

doi:10.3892/ijo.2015.2946

The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway

Authors:
- Jianchu 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
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Affiliations: College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, P.R. China, Department of Pharmaceutical Science, West Virginia University, Morgantown, WV 26506, USA, Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA, College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA
Published online on: April 1, 2015 https://doi.org/10.3892/ijo.2015.2946
Pages: 2629-2638

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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.

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