Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in lewis lung carcinoma-bearing mice.
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.
Lee
Hyo-Jung
HJ
Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyunghee University, Seoul, South Korea.
Lee
Hyo-Jeong
HJ
Magesh
Venkataraman
V
Nam
Dongwoo
D
Lee
Eun-Ok
EO
Ahn
Kwang Seok
KS
Jung
Min-Hyung
MH
Ahn
Kyoo-Seok
KS
Kim
Dae-Keun
DK
Kim
Ji-Young
JY
Kim
Sung-Hoon
SH
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
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