The anti-cancer effects of itraconazole in epithelial ovarian cancer
Autor: | Joon-Yong Chung, Kris Ylaya, Ji-Yoon Ryu, Jung-Joo Choi, Yoo-Young Lee, Stephen M. Hewitt, Byoung-Gie Kim, Jeong-Won Lee, Chel Hun Choi, Hye-Kyung Jeon, Duk-Soo Bae, Tae-Joong Kim, Young Jae Cho |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Paclitaxel Angiogenesis Itraconazole Science Antineoplastic Agents Pharmacology Carcinoma Ovarian Epithelial Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine GLI1 medicine Animals Hedgehog PI3K/AKT/mTOR pathway Cell Proliferation Multidisciplinary biology Endothelial Cells Drug Synergism Endothelial stem cell Disease Models Animal 030104 developmental biology Treatment Outcome chemistry 030220 oncology & carcinogenesis Cancer cell biology.protein Medicine Heterografts Female Neoplasm Transplantation medicine.drug |
Zdroj: | Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) |
ISSN: | 2045-2322 |
Popis: | We assessed the anti-proliferative activity of itraconazole using an EOC cell line (SKOV3ip1) and endothelial cell lines (HUVEC & SVEC4-10). We also examined angiogenesis (VEGFR2, p-ERK, p-PLCr1/2), hedgehog (Gli1, Ptch1, SMO), and mTOR (pS6K1) signaling pathways to determine the mechanism of action of itraconazole. Furthermore, we evaluated the synergistic effects of itraconazole and paclitaxel using orthotopic mouse models with established EOC cells (SKOV3ip1 or HeyA8) as well as patient-derived xenografts (PDXs). Itraconazole treatment inhibited proliferation of endothelial cells in a dose-dependent manner, but had no effect on EOC cells. The endothelial cell antiproliferative effect was associated with inhibition of hedgehog, and mTOR pathways and angiogenesis. In xenograft models of EOC using SKOV3ip1 or HeyA8, mice treated with the combination of itraconazole and paclitaxel had significantly decreased tumor weight than the control, paclitaxel-alone, or itraconazole-alone groups. Tissue derived from these tumors had significantly lower microvessel density than tissue from the other groups as well as hedgehog and mTOR pathway inhibition. We confirmed those effects in two EOC PDX models. These results suggest that itraconazole selectively inhibits endothelial cells rather than cancer cells by targeting multiple pathways including hedgehog, and mTOR pathways and angiogenesis. |
Databáze: | OpenAIRE |
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