Masayasu Hara1, Takaya Nagasaki2, Kazuyoshi Shiga2, Hiromitsu Takeyama2. 1. Department of Gastroenterological Surgery, Nagoya City University, Mizuho-cho, Mizuho-ku, Nagoya, Japan mshara@med.nagoya-cu.ac.jp. 2. Department of Gastroenterological Surgery, Nagoya City University, Mizuho-cho, Mizuho-ku, Nagoya, Japan.
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). MATERIALS AND 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. CONCLUSION: Itraconazole-dependent suppression of endothelial cell and CAF growth resulted in synergistic effects with bevacizumab in bevacizumab-resistant cancer cells. Copyright
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). MATERIALS AND METHODS:Humangastrointestinal cancer cell lines (HT-29, MKN-28 and MKN-45), human umbilical vein endothelial cells (HUVECs), and CAFs established from humancolon 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. CONCLUSION:Itraconazole-dependent suppression of endothelial cell and CAF growth resulted in synergistic effects with bevacizumab in bevacizumab-resistant cancer cells. Copyright
Authors: Simon J A Buczacki; Semiramis Popova; Emma Biggs; Chrysa Koukorava; Jon Buzzelli; Louis Vermeulen; Lee Hazelwood; Hayley Francies; Mathew J Garnett; Douglas J Winton Journal: J Exp Med Date: 2018-05-31 Impact factor: 14.307
Authors: Dennis Gürgen; Theresia Conrad; Michael Becker; Susanne Sebens; Christoph Röcken; Jens Hoffmann; Stefan Langhammer Journal: Commun Biol Date: 2022-01-17