title: Antitumor and antimetastatic actions of xanthoangelol and 4-hydroxyderricin isolated from Angelica keiskei roots through the inhibited activation and differentiation of M2 macrophages.
abstract: BACKGROUND
  Tumor growth and metastasis have been closely associated with the M2 macrophage-induced activation of tumor-associated macrophages (TAMs).
  
  
  OBJECTIVE
  The antitumor and antimetastatic actions of xanthangelol and 4-hydroxyderricin on the role of M2 macrophages in the TAMs of highly metastatic osteosarcoma LM8-bearing mice have not yet been fully elucidated. In order to clarify the mechanisms underlying the antitumor and antimetastatic actions of the above chalcones, we performed in vivo and in vitro studies.
  
  
  METHODS
  The antitumor and antimetastatic actions of xanthoangelol and 4-hydroxyderricin were examined in vivo and the effects on M2 macrophage differentiation and activation were examined in vitro.
  
  
  METHODS
  We examined the antitumor and antimetastatic effects of xanthoangelol and 4-hydroxyderricin on highly metastatic osteosarcoma LM8-bearing mice (in vivo). Further, we examined their effects on the differentiation of interleukin (IL)-4 plus IL-13-induced M2 macrophages and activation of IL-4 plus IL13-induced M2 macrophages (in vitro). We also investigated the expression and phosphorylation of signal transducer and activator of transcript 3 (Stat 3) in the differentiation process of M2-polarized macrophages (in vitro).
  
  
  RESULTS
  Xanthoangelol or 4-hydroxyderricin (25 or 50 mg/kg, twice daily) inhibited tumor growth, metastasis to the lung and liver, and TAM expression in tumors. In addition, xanthoangelol (10, 25 or 50 μM) and 4-hydroxyderricin (5, 10, 25 or 50 μM) inhibited the production of IL-10 and monocyte chemoattractant protein (MCP)-1 in M2-polarized macrophages. This result indicated that xanthoangelol and 4-hydroxyderricin inhibited the activation of M2 macrophages. Furthermore, xanthoangelol (5-50 μM) inhibited the phosphorylation of Stat 3 without affecting the expression of the Stat 3 protein in the differentiation process of M2 macrophages, which indicated that these chalcones inhibited the differentiation of M2 macrophages.
  
  
  CONCLUSIONS
  These findings suggested that the antitumor and antimetastatic actions of xanthoangelol and 4-hydroxyderrcin might be attributed to the regulated activated TAMs through the inhibition of activation and differentiation of M2 macrophages in the tumor microenvironment.
authors.affiliation: Division of Functional Histology, Department of Functional Biomedicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0295, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Sumiyoshi
authors.affiliation: Department of Pharmacognosy, Osaka University of Pharmaceutical Sciences, Takatsuki City, Osaka 569-1094, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Pharmacognosy, Osaka University of Pharmaceutical Sciences, Takatsuki City, Osaka 569-1094, Japan.
authors.forename: Kimiye
authors.initials: K
authors.lastname: Baba
authors.affiliation: Division of Biochemical Pharmacology, Department of Basic Medical Research, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0295, Japan . Electronic address: yokim@m.ehime-u.ac.jp.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kimura
mesh_terms: D029969:Angelica / Q000737:chemistry*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000473:pathology; D018517:Plant Roots / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C508609:IL10 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; C068243:4-hydroxyderricin; D002599:Chalcone; C068244:xanthoangelol
keywords: Antimetastatic; Antitumor; Chalcones; M2 macrophage; Stat3