Shikonin, Acetylshikonin, and Isobutyroylshikonin Inhibit VEGF-induced Angiogenesis and Suppress Tumor Growth in Lewis Lung Carcinoma-bearing Mice

Hyo-Jung LEE; Hyo-Jeong LEE; Venkataraman MAGESH; Dongwoo NAM; Eun-Ok LEE; Kwang Seok AHN; Min-Hyung JUNG; Kyoo-Seok AHN; Dae-Keun KIM; Ji-Young KIM; Sung-Hoon KIM

doi:10.1248/yakushi.128.1681

Regular Articles

Shikonin, Acetylshikonin, and Isobutyroylshikonin Inhibit VEGF-induced Angiogenesis and Suppress Tumor Growth in Lewis Lung Carcinoma-bearing Mice

Hyo-Jung LEE, Hyo-Jeong LEE, Venkataraman MAGESH, Dongwoo NAM, Eun-Ok LEE, Kwang Seok AHN, Min-Hyung JUNG, Kyoo-Seok AHN, Dae-Keun KIM, Ji-Young KIM, Sung-Hoon KIM

Author information

Hyo-Jung LEE
Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University
Hyo-Jeong LEE
Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University
Venkataraman MAGESH
Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University
Dongwoo NAM
Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University
Eun-Ok LEE
Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University
Kwang Seok AHN
Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University
Min-Hyung JUNG
College of Medicine, Kyunghee University
Kyoo-Seok AHN
Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University
Dae-Keun KIM
College of Pharmacy, Woosuk University
Ji-Young KIM
Graduate School of Biotechnology and Institute of Life Sciences and Resources, Kyunghee University
Sung-Hoon KIM
Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University

Keywords: lithospermum erythrorhizon, shikonin derivative, angiogenesis, vascular endothelial growth factor (VEGF)

JOURNAL FREE ACCESS

2008 Volume 128 Issue 11 Pages 1681-1688

DOI https://doi.org/10.1248/yakushi.128.1681

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Abstract

Lithospermum erythrorhizon has been used for treatment of inflammatory diseases and cancer as a folk remedy. Based on the evidences that anti-inflammatory agents frequently exert antiangiogenic activity, thus we examined comparatively the antiangiogenic activities of three naphthoquinone derivatives (shikonin, acetylshikonin, and isobutyroylshikonin) isolated from the plant. Three derivatives exhibited weak cytotoxicity against human umbilical vein endothelial cells (HUVECs) with IC₅₀ of over 20 μM. Shikonin had more specific inhibitory effects on proliferation and vascular endothelial growth factor (VEGF) production by VEGF compared with different derivatives. All of derivatives significantly suppressed the migration of VEGF treated HUVECs at different optimal concentrations. Also, shikonin and acetylshikonin significantly disrupted VEGF-induced tube formation. Furthermore, three derivatives effectively downregulated the expression of urokinase-type plasminogen activator (uPA), but not its receptor uPAR. Additionally, shikonin significantly inhibited tumor growth in LLC-bearing mice, whereas its derivatives had relatively mild effects. Taken together, our findings suggest that shikonin and its derivatives exhibit the antiangiogenic and antitumorigenic effects by suppressing proliferation and angiogenic factors.

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