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.