Journal Article

Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of <i>Vitis amurensis</i> through apoptotic and anti-angiogenic activities

Eun-Ok Lee, Hyo-Jung Lee, Hwa-Soo Hwang, Kyoo-Seok Ahn, Chanhee Chae, Kyung-Sun Kang, Junxuan Lu and Sung-Hoon Kim

in Carcinogenesis

Volume 27, issue 10, pages 2059-2069
ISSN: 0143-3334
Published online May 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl055
Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities

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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 antitumor activity of HA using the mouse Lewis lung carcinoma (LLC) model. We administered HA and RES by daily intraperitonial 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 anticancer 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-induced cleavage of caspase-9 and caspase-3 and PARP were completely blocked by a pan caspase inhibitor, Z-VAD-FMK. In addition, HA and RES suppressed the basic fibroblast growth factor (bFGF)-induced proliferation and capillary differentiation of human umbilical vein endothelial cells, and 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 anticancer compound that induces caspase-mediated cancer cell apoptosis and inhibits angiogenesis rivaling the potency of RES and merits further evaluation for cancer chemoprevention.

Journal Article.  6465 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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