title: 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.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University, Seoul, South Korea.
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Magesh
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Nam
authors.forename: Eun-Ok
authors.initials: EO
authors.lastname: Lee
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Min-Hyung
authors.initials: MH
authors.lastname: Jung
authors.forename: Kyoo-Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Dae-Keun
authors.initials: DK
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D029684:Lithospermum / Q000737:chemistry; D051379:Mice; D009285:Naphthoquinones / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D000880:Anthraquinones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009285:Naphthoquinones; D042461:Vascular Endothelial Growth Factor A; C534260:isobutyroylshikonin; C016101:shikonin; D014568:Urokinase-Type Plasminogen Activator; C073944:acetylshikonin