title: Anti-tumor and anti-metastatic actions of wogonin isolated from Scutellaria baicalensis roots through anti-lymphangiogenesis.
abstract: Tumor growth and metastasis are associated with angiogenesis and lymphangiogenesis through the production of vascular endothelial growth factor (VEGF) or VEGF-C in tumors, and the phosphorylation of VEGF receptor (VEGFR)-2 or VEGFR-3 in vascular endothelial cells or lymphatic endothelial cells (LECs). Tumor-associated macrophages (TAMs) play an important role in tumor lymphangiogenesis, and consequently stimulate metastasis through the lymphatic system to lymph nodes. We examined the effects of wogonin isolated from Scutellaria baicalensis roots on tumor growth and metastasis using a highly metastatic model in osteosarcoma LM8-bearing mice. Wogonin (25 and 50 mg/kg, twice daily) reduced tumor growth and metastasis to the lung, liver and kidney, angiogenesis (CD31-positive cells), lymphangiogenesis (LYVE-1-positive cells), and TAM (F4/80-positive cell) numbers in the tumors of LM8-bearing mice. Wogonin (10-100 μM) also inhibited increases in IL-1β production and cyclooxygenase (COX)-2 expression induced by lipopolysaccharide in THP-1 macrophages. Wogonin had no effect on VEGF-C production in LM8 cells, or VEGFR-3 expression in human lymphatic endothelial cells (HLECs), however, it inhibited VEGF-C-induced VEGFR-3 phosphorylation in HLECs. The anti-tumor and anti-metastatic actions of wogonin may be associated with the inhibition of VEGF-C-induced lymphangiogenesis through a reduction in VEGF-C-induced VEGFR-3 phosphorylation by the inhibition of COX-2 expression and IL-1β production in TAMs.
authors.affiliation: Division of Biochemical Pharmacology, Department of Basic Medical Research, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime, Japan. yokim@m.ehime-u.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kimura
authors.forename: Maho
authors.initials: M
authors.lastname: Sumiyoshi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D044950:Flavanones / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D008517:Phytotherapy; D018517:Plant Roots / Q000737:chemistry; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D031364:Scutellaria baicalensis / Q000737:chemistry*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018932:Chemokine CCL2; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D044950:Flavanones; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042582:Vascular Endothelial Growth Factor C; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D040321:Vascular Endothelial Growth Factor Receptor-3; C085514:wogonin