Suppression of Cancer-associated Fibroblasts and Endothelial Cells by Itraconazole in Bevacizumab-resistant Gastrointestinal Cancer.

We evaluated the ability of itraconazole to enhance the effects of bevacizumab in bevacizumab-resistant cancer cells, endothelial cells, and cancer-associated fibroblasts (CAFs). 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. 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. Itraconazole-dependent suppression of endothelial cell and CAF growth resulted in synergistic effects with bevacizumab in bevacizumab-resistant cancer cells.