PMID- 30381665
OWN - NLM
STAT- MEDLINE
DCOM- 20190214
LR  - 20190215
IS  - 1347-5215 (Electronic)
IS  - 0918-6158 (Linking)
VI  - 41
IP  - 11
DP  - 2018
TI  - Shikonin Suppresses Lymphangiogenesis via NF-kappaB/HIF-1alpha Axis Inhibition.
PG  - 1659-1666
LID - 10.1248/bpb.b18-00329 [doi]
AB  - 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-kappaB) activation, as indicated by 
      phosphorylation and nuclear translocation of NF-kappaB p65, and also reduced both 
      mRNA and protein levels of hypoxia-inducible factor-1 (HIF-1)alpha. Use of an NF-kappaB 
      inhibitor (BAY 11-7085) and HIF-1alpha small interfering RNA (siRNA) transfection 
      revealed that NF-kappaB activation was upstream of HIF-1alpha 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-kappaB/HIF-1alpha pathway and involves in suppression of VEGF-C and VEGFR-3 mRNA 
      expression.
FAU - Prangsaengtong, Orawin
AU  - Prangsaengtong O
AD  - Department of Biopharmacy, Faculty of Pharmacy, Srinakharinwirot University.
FAU - Jantaree, Phatcharida
AU  - Jantaree P
AD  - Laboratory of Biochemistry, Chulabhorn Research Institute.
FAU - Lirdprapamongkol, Kriengsak
AU  - Lirdprapamongkol K
AD  - Laboratory of Biochemistry, Chulabhorn Research Institute.
FAU - Svasti, Jisnuson
AU  - Svasti J
AD  - Laboratory of Biochemistry, Chulabhorn Research Institute.
FAU - Koizumi, Keiichi
AU  - Koizumi K
AD  - Department of Kampo Diagnostics, Institute of Natural Medicine, University of 
      Toyama.
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - Biol Pharm Bull
JT  - Biological & pharmaceutical bulletin
JID - 9311984
RN  - 0 (Drugs, Chinese Herbal)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NF-kappa B)
RN  - 0 (Naphthoquinones)
RN  - 0 (RNA, Messenger)
RN  - 0 (Vascular Endothelial Growth Factor C)
RN  - 3IK6592UBW (shikonin)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-3)
SB  - IM
MH  - Drugs, Chinese Herbal/*pharmacology/therapeutic use
MH  - Endothelial Cells/drug effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Lithospermum/*chemistry
MH  - Lymphangiogenesis/*drug effects
MH  - Lymphatic Metastasis/prevention & control
MH  - NF-kappa B/*metabolism
MH  - Naphthoquinones/*pharmacology/therapeutic use
MH  - Phytotherapy
MH  - RNA, Messenger/metabolism
MH  - Vascular Endothelial Growth Factor C/genetics/metabolism
MH  - Vascular Endothelial Growth Factor Receptor-3/genetics/metabolism
OTO - NOTNLM
OT  - hypoxia-inducible factor-1 (HIF-1)
OT  - in vitro
OT  - lymphangiogenesis
OT  - nuclear factor-kappaB (NF-kappaB)
OT  - shikonin
EDAT- 2018/11/02 06:00
MHDA- 2019/02/15 06:00
CRDT- 2018/11/02 06:00
PHST- 2018/11/02 06:00 [entrez]
PHST- 2018/11/02 06:00 [pubmed]
PHST- 2019/02/15 06:00 [medline]
AID - 10.1248/bpb.b18-00329 [doi]
PST - ppublish
SO  - Biol Pharm Bull. 2018;41(11):1659-1666. doi: 10.1248/bpb.b18-00329.