Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in lewis lung carcinoma-bearing mice.

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 microM. 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.

• Authors: 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
• Journal: Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan (Yakugaku Zasshi) Vol. 128 Issue 11 Pg. 1681-8 (Nov 2008) ISSN: 0031-6903 [Print] Japan
• PMID: 18981704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthraquinones
• Anti-Inflammatory Agents, Non-Steroidal
• Naphthoquinones
• Vascular Endothelial Growth Factor A
• isobutyroylshikonin
• shikonin
• Urokinase-Type Plasminogen Activator
• acetylshikonin

Topics

• Animals
• Anthraquinones (isolation & purification, pharmacology, therapeutic use)
• Anti-Inflammatory Agents, Non-Steroidal (isolation & purification, pharmacology, therapeutic use)
• Carcinoma, Lewis Lung (drug therapy)
• Cell Movement (drug effects)
• Cells, Cultured
• Depression, Chemical
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Endothelial Cells (drug effects)
• Female
• Humans
• Lithospermum (chemistry)
• Mice
• Naphthoquinones (isolation & purification, pharmacology, therapeutic use)
• Neovascularization, Pathologic
• Urokinase-Type Plasminogen Activator (metabolism)
• Vascular Endothelial Growth Factor A (pharmacology)