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

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2059-2069
Number of pages11
JournalCarcinogenesis
Volume27
Issue number10
DOIs
StatePublished - Oct 1 2006

Fingerprint

Vitis
Lung Neoplasms
Growth
Lewis Lung Carcinoma
Neoplasms
Fibroblast Growth Factor 2
Apoptosis
Caspase 3
Vitaceae
Cell Culture Techniques
East Asian Traditional Medicine
heyneanol A
Caspase Inhibitors
Angiogenesis Inhibitors
resveratrol
Caspase 9
Herbal Medicine
Human Umbilical Vein Endothelial Cells
Chemoprevention
In Situ Nick-End Labeling

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Lee, Eun Ok ; Lee, Hyo Jung ; Hwang, Hwa Soo ; Ahn, Kyoo Seok ; Chae, Chanhee ; Kang, Kyung Sun ; Lu, Junxuan ; Kim, Sung Hoon. / Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. In: Carcinogenesis. 2006 ; Vol. 27, No. 10. pp. 2059-2069.
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abstract = "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.",
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Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. / Lee, Eun Ok; Lee, Hyo Jung; Hwang, Hwa Soo; Ahn, Kyoo Seok; Chae, Chanhee; Kang, Kyung Sun; Lu, Junxuan; Kim, Sung Hoon.

In: Carcinogenesis, Vol. 27, No. 10, 01.10.2006, p. 2059-2069.

Research output: Contribution to journalArticle

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T1 - Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities

AU - Lee, Eun Ok

AU - Lee, Hyo Jung

AU - Hwang, Hwa Soo

AU - Ahn, Kyoo Seok

AU - Chae, Chanhee

AU - Kang, Kyung Sun

AU - Lu, Junxuan

AU - Kim, Sung Hoon

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AB - 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.

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