title: Suppression of Cancer-associated Fibroblasts and Endothelial Cells by Itraconazole in Bevacizumab-resistant Gastrointestinal Cancer.
abstract: BACKGROUND
  We evaluated the ability of itraconazole to enhance the effects of bevacizumab in bevacizumab-resistant cancer cells, endothelial cells, and cancer-associated fibroblasts (CAFs).
  
  
  METHODS
  Human gastrointestinal cancer cell lines (HT-29, MKN-28 and MKN-45), human umbilical vein endothelial cells (HUVECs), and CAFs established from human colon cancer were used. In each of these cell lines, cell growth, apoptosis, and angiogenesis were evaluated with bevacizumab with and without itraconazole both in vitro and in vivo.
  
  
  RESULTS
  Itraconazole suppressed HUVEC growth by apoptosis through inhibition of mitogen-activated protein kinase and ribosomal protein S6 kinase signaling. Itraconazole also suppressed monocyte chemoattractant protein-1 secretion and the growth of CAFs. In xenografts, compared to monotherapy with either agent alone, combined treatment with itraconazole and bevacizumab significantly reduced tumor volume, tumor weight, and microvessel density.
  
  
  CONCLUSIONS
  Itraconazole-dependent suppression of endothelial cell and CAF growth resulted in synergistic effects with bevacizumab in bevacizumab-resistant cancer cells.
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, Mizuho-cho, Mizuho-ku, Nagoya, Japan mshara@med.nagoya-cu.ac.jp.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Hara
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Nagasaki
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Shiga
authors.affiliation: Department of Gastroenterological Surgery, Nagoya City University, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takeyama
mesh_terms: D000818:Animals; D000068258:Bevacizumab / Q000627:therapeutic use*; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D017964:Itraconazole / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude
chemical_list: D000068258:Bevacizumab; D017964:Itraconazole
keywords: Angiogenesis; bevacizumab resistance; colorectal cancer; gastric cancer; itraconazole