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Title: Shikonin suppresses lymphangiogenesis via NF-κB/HIF-1α axis inhibition
Authors: Prangsaengtong O.
Jantaree P.
Lirdprapamongkol K.
Svasti J.
Koizumi K.
Keywords: 3 (4 tert butylphenylsulfonyl) 2 propenenitrile
hypoxia inducible factor 1alpha
immunoglobulin enhancer binding protein
messenger RNA
small interfering RNA
synaptotagmin I
vasculotropin C
vasculotropin receptor 3
herbaceous agent
hypoxia inducible factor 1alpha
immunoglobulin enhancer binding protein
messenger RNA
vasculotropin C
vasculotropin receptor 3
cancer inhibition
concentration (parameters)
controlled study
endothelium cell
genetic transfection
human cell
in vitro study
lymph vessel endothelium
nucleocytoplasmic transport
protein phosphorylation
Western blotting
drug effect
lymph node metastasis
Drugs, Chinese Herbal
Endothelial Cells
Hypoxia-Inducible Factor 1, alpha Subunit
Lymphatic Metastasis
NF-kappa B
RNA, Messenger
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor Receptor-3
Issue Date: 2018
Abstract: Lymphangiogenesis, the formation of lymphatic vessels from preexisting ones, promotes cancer growth and metastasis. Finding natural compounds with anti-lymphangiogenic activity will be useful for preventive treatment of lymphatic metastasis. Shikonin, an ingredient of a traditional Japanese and Chinese medicinal herb Lithospermum erythrorhizon, has been widely used in several pharmaceutical and cosmetic preparations, as well as in food colorants. Shikonin has been reported to inhibit lymphangiogenesis in vitro, but the mechanism of inhibition has not been determined. The aim of this study is to investigate the mechanism of anti-lymphangiogenesis of shikonin in primary human lymphatic endothelial cells (HMVEC-dLy). Shikonin, at non-toxic concentrations, significantly inhibited cord formation ability of lymphatic endothelial cells in a dose- and time-dependent manner. Western blotting analysis showed that shikonin decreased nuclear factor-kappaB (NF-κB) activation, as indicated by phosphorylation and nuclear translocation of NF-κB p65, and also reduced both mRNA and protein levels of hypoxia-inducible factor-1 (HIF-1)α. Use of an NF-κB inhibitor (BAY 11-7085) and HIF-1α small interfering RNA (siRNA) transfection revealed that NF-κB activation was upstream of HIF-1α expression, which controls cord formation by HMVEC-dLy. In addition, the reduction of vascular endothelial growth factor C (VEGF-C) and vascular endothelial growth factor receptor-3 (VEGFR-3) mRNA levels were also found in HMVEC-dLy that treated with shikonin. In conclusion, shikonin inhibits lymphangiogenesis in vitro by interfering the NF-κB/HIF-1α pathway and involves in suppression of VEGF-C and VEGFR-3 mRNA expression. © 2018 The Pharmaceutical Society of Japan
ISSN: 9186158
Appears in Collections:Scopus 1983-2021

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