Acetylshikonin

Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in lewis lung carcinoma-bearing mice.[Pubmed: 18981704]

Yakugaku Zasshi. 2008 Nov;128(11):1681-8.

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.
METHODS AND RESULTS:
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.
CONCLUSIONS:
Taken together, our findings suggest that shikonin and its derivatives exhibit the antiangiogenic and antitumorigenic effects by suppressing proliferation and angiogenic factors.

Anti-inflammatory activity of shikonin derivatives from Arnebia hispidissima.[Pubmed: 12834001]

Phytomedicine. 2003;10(5):375-80.

Arnebia hispidissima ethanolic extract, after chromatography, yielded a number of shikonin derivatives, which were identified as arnebin-5, arnebin-6, teracryl shikonin, arnebinone and Acetylshikonin.
METHODS AND RESULTS:
All these compounds were firstly reported from this plant species and evaluated to the anti-inflammatory activity of ethanolic extract and isolated shikonin derivatives, models with carrageenan-induced paw edema and complete Freund's adjuvant (CFA)-induced chronic arthritis in rats were conducted.
CONCLUSIONS:
The observed results indicated that pre-treatment with arnebinone significantly inhibited the carrageenan-induced paw edema and also suppressed the development of chronic arthritis induced by CFA.

Modulation of orphan nuclear receptor Nur77-mediated apoptotic pathway by acetylshikonin and analogues.[Pubmed: 18974131]

Cancer Res. 2008 Nov 1;68(21):8871-80.

Shikonin derivatives, which are the active components of the medicinal plant Lithospermum erythrorhizon, exhibit many biological effects including apoptosis induction through undefined mechanisms. We recently discovered that orphan nuclear receptor Nur77 migrates from the nucleus to the mitochondria, where it binds to Bcl-2 to induce apoptosis.
METHODS AND RESULTS:
Here, we report that certain shikonin derivatives could modulate the Nur77/Bcl-2 apoptotic pathway by increasing levels of Nur77 protein and promoting its mitochondrial targeting in cancer cells. Structural modification of Acetylshikonin resulted in the identification of a derivative 5,8-diacetoxyl-6-(1'-acetoxyl-4'-methyl-3'-pentenyl)-1,4-naphthaquinones (SK07) that exhibited improved efficacy and specificity in activating the pathway. Unlike other Nur77 modulators, shikonins increased the levels of Nur77 protein through their posttranscriptional regulation. The apoptotic effect of SK07 was impaired in Nur77 knockout cells and suppressed by cotreatment with leptomycin B that inhibited Nur77 cytoplasmic localization. Furthermore, SK07 induced apoptosis in cells expressing the COOH-terminal half of Nur77 protein but not its NH(2)-terminal region. Our data also showed that SK07-induced apoptosis was associated with a Bcl-2 conformational change and Bax activation.
CONCLUSIONS:
Together, our results show that certain shikonin derivatives act as modulators of the Nur77-mediated apoptotic pathway and identify a new shikonin-based lead that targets Nur77 for apoptosis induction.

Biol. Pharmaceut. Bull., 1994, 17(8):1075-7.

Accelerative effect of shikonin, alkannin and acetylshikonin on the proliferation of granulation tissue in rats.[Pubmed: 7820111]

METHODS AND RESULTS:
The present study was carried out to compare the accelerative effect of shikonin (R-type), alkannin (S-type), and Acetylshikonin on the proliferation of granulation tissue in rats, and to elucidate the correlation between the potency of the effect and their optical activity. Koushikon mainly contained the R-type of Acetylshikonin, and Nanshikon mainly contained the S-type of Acetylshikonin. Each compound produced a dose-dependent acceleration of the cotton pellet-induced granuloma formation. In comparing identical doses of shikonin, alkannin and Acetylshikonin, the potency of their accelerative effects on the proliferation of granulation tissue was about the same.
CONCLUSIONS:
This result suggests that their absolute configurations (R-type or S-type) and their acetylation on the hydroxy group of the sidechain of shikonin or alkannin may not be important in producing the effect.