Carcinogenesis Advance Access published online on May 4, 2006
Carcinogenesis, doi:10.1093/carcin/bgl055
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1 College of Oriental Medicine, Kyunghee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 131-701, Republic of Korea
* To whom correspondence should be addressed. Vitis amurensis Rupr. (Vitaceae) has long been used in Chinese/Oriental herbal medicine for the treatment of cancer, but its active compounds and mechanisms of action have not been well studied. To this end, we isolated from its root heyneanol A (HA), which is a tetramer of resveratrol (RES), and established the in vivo anti-tumor activity of HA using the mouse Lewis Lung Carcinoma (LLC) model. We administered HA and RES by daily i.p. injection to C57BL/6 mice that were subcutaneously inoculated with LLC cells. HA dose-dependently decreased tumor growth without any adverse effect on body weight and seemed more potent than RES. The tumor inhibitory effects were accompanied by a marked increase in tumor cell apoptosis detected by cleaved caspase-3 and TUNEL assays and decreased tumor cell proliferation index and tumor microvessel density, supporting the involvement of apoptotic and anti-angiogenic activities in the anti-cancer effects. We next investigated the cellular and molecular processes that mediate the apoptosis and anti-angiogenesis effects using cell culture models. Mechanistically, treatment of LLC cells in vitro with HA or RES significantly increased apoptotic cells. Both HA and RES activated caspase-9 and caspase-3, caused PARP cleavage, which were completely blocked by a pan caspase inhibitor, Z-VAD-FMK. In addition, HA and RES suppressed the bFGF-induced proliferation and capillary differentiation of human umbilical vein endothelial cells, inhibited the binding of bFGF to its receptor in a test tube assay and the bFGF-induced vascularization of Matrigel plugs in vivo. Remarkably, HA was fairly stable in cell culture medium and did not undergo intracellular conversion to RES. Therefore, HA is an active anti-cancer compound that induces caspase-mediated cancer cell apoptosis and inhibits angiogenesis rivaling the potency of RES and merits further evaluation for cancer chemoprevention.
Received December 6, 2005
Revised March 2, 2006
Accepted April 13, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities
Eun-Ok Lee 1,
Hyo-Jung Lee 1,
Kyoo-Seok Ahn 1,
Chanhee Chae 2,
Kyung-Sun Kang 2,
Junxuan Lu 3 *,
and
Sung-Hoon Kim 1
2 College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
3 Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA
Junxuan Lu, E-mail: jlu{at}hi.umn.edu
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