|Lu, Jianming -|
|Zhang, Keqiang -|
|Nam, S -|
|Jove, Richard -|
|Wen, W -|
Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 18, 2009
Publication Date: March 1, 2010
Citation: Lu, J., Zhang, K., Nam, S., Anderson, R.A., Jove, R., Wen, W. 2010. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling. Carcinogenesis. 31:481-488. Interpretive Summary: Human tumors can remain dormant for years owing to the balance between cell growth and controlled cell death. Concentrations of inhibitors that prevent uncontrolled cell growth exceeding that of stimulators could prevent tumors from growing, as well as from spreading to other organs. For tumor cells to grow, a newly developed blood supply is needed. Blockade of the growth of this new blood supply is therefore an important approach for cancer treatment and prevention. A factor circulated in the blood called vascular endothelial growth factor (VEGF)is one of the most critical factors that promotes the formation of new blood vessels (angiogenesis), a critical requirement to support tumor growth. VEGF has emerged as an attractive target for anti-cancer treatment. However, most of current anti-VEGF agents often cause side effects when given over a long term. Identification of natural VEGF inhibitors derived from foods that are not only effective, but also safe and without side effects is underway. In this study, an extract of cinnamon, and specific components of cinnamon, were shown to effectively inhibit the formation of a new blood supply needed for tumor cells. This has the potential to lead to the alleviation and prevention of many forms of cancer. This work is important to the scientific community involved in the prevention and treatment of cancer, but also to the millions of people who may develop cancer.
Technical Abstract: VEGF is one of the most critical factors that induce angiogenesis, and has thus become an attractive target for anti-angiogenesis treatment. However, most of the current anti-VEGF agents that often cause side effects cannot be recommended for long term use. Identification of natural VEGF inhibitors derived from foods would be one alternative approach with an advantage of anticipated safety. To isolate natural inhibitors of VEGF activity, an in vitro tyrosine kinase assay to screen for diet-based agents that suppress VEGFR kinase activity was employed. An extract from cinnamon (CE), one of the most popular and the oldest spices, was found to be a potent inhibitor of VEGFR kinase activity, which directly inhibited kinase activity of purified VEGFR2- and VEGFR/MAPK-mediated signaling pathways in endothelial cells. As a result, CE inhibited VEGF-induced endothelial cell proliferation, migration, and tube formation in vitro, sprouts formation from the aortic ring ex vivo, and tumor-induced blood vessel formation in vivo. Depletion of polyphenols from CE with polyvinylpyrrolidone (PVPP) abolished its anti-angiogenesis activity. While cinnamaldehyde, a component associated with the aroma of CE, had little effect on VEGFR kinase activity, HPLC-purified components of CE, procyanidin type-A trimer (MW, 864) and a tetramer (MW, 1152) were found to inhibit kinase activity of purified VEGFR- and VEGFR-signaling pathways. These data suggested that procyanidin oligomers are the active components in CE that inhibit angiogenesis. Taken together, this study revealed a novel activity in cinnamon and identified a natural inhibitor of VEGF signaling that could potentially be useful in cancer prevention and/or treatment.