The anti-cancer effects of itraconazole in epithelial ovarian cancer

The anti-cancer effects of itraconazole in epithelial ovarian cancer

Abstract 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 mechan...

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Autores principales: Chel Hun Choi, Ji-Yoon Ryu, Young-Jae Cho, Hye-Kyung Jeon, Jung-Joo Choi, Kris Ylaya, Yoo-Young Lee, Tae-Joong Kim, Joon-Yong Chung, Stephen M. Hewitt, Byoung-Gie Kim, Duk-Soo Bae, Jeong-Won Lee
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Lenguaje:EN
Publicado: Nature Portfolio 2017
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Science
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Acceso en línea:https://doaj.org/article/e5ea0a7065c94edd9f99bdda3322c4ca
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spelling oai:doaj.org-article:e5ea0a7065c94edd9f99bdda3322c4ca2021-12-02T11:52:42ZThe anti-cancer effects of itraconazole in epithelial ovarian cancer10.1038/s41598-017-06510-72045-2322https://doaj.org/article/e5ea0a7065c94edd9f99bdda3322c4ca2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06510-7https://doaj.org/toc/2045-2322Abstract 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.Chel Hun ChoiJi-Yoon RyuYoung-Jae ChoHye-Kyung JeonJung-Joo ChoiKris YlayaYoo-Young LeeTae-Joong KimJoon-Yong ChungStephen M. HewittByoung-Gie KimDuk-Soo BaeJeong-Won LeeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Chel Hun Choi
Ji-Yoon Ryu
Young-Jae Cho
Hye-Kyung Jeon
Jung-Joo Choi
Kris Ylaya
Yoo-Young Lee
Tae-Joong Kim
Joon-Yong Chung
Stephen M. Hewitt
Byoung-Gie Kim
Duk-Soo Bae
Jeong-Won Lee
The anti-cancer effects of itraconazole in epithelial ovarian cancer
description Abstract 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.
format article
author Chel Hun Choi
Ji-Yoon Ryu
Young-Jae Cho
Hye-Kyung Jeon
Jung-Joo Choi
Kris Ylaya
Yoo-Young Lee
Tae-Joong Kim
Joon-Yong Chung
Stephen M. Hewitt
Byoung-Gie Kim
Duk-Soo Bae
Jeong-Won Lee
author_facet Chel Hun Choi
Ji-Yoon Ryu
Young-Jae Cho
Hye-Kyung Jeon
Jung-Joo Choi
Kris Ylaya
Yoo-Young Lee
Tae-Joong Kim
Joon-Yong Chung
Stephen M. Hewitt
Byoung-Gie Kim
Duk-Soo Bae
Jeong-Won Lee
author_sort Chel Hun Choi
title The anti-cancer effects of itraconazole in epithelial ovarian cancer
title_short The anti-cancer effects of itraconazole in epithelial ovarian cancer
title_full The anti-cancer effects of itraconazole in epithelial ovarian cancer
title_fullStr The anti-cancer effects of itraconazole in epithelial ovarian cancer
title_full_unstemmed The anti-cancer effects of itraconazole in epithelial ovarian cancer
title_sort anti-cancer effects of itraconazole in epithelial ovarian cancer
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/e5ea0a7065c94edd9f99bdda3322c4ca
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