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Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma

Recent evidence demonstrates that the efficacy of conventional anticancer therapies including chemotherapy requires a functional immune system. Here, we addressed the possibility that the antitumor effect of a selective Smoothened antagonist and Hedgehog (Hh) pathway inhibitor (LDE225), a promising...

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Autores principales: Paget, Christophe, Duret, Helene, Ngiow, Shin Foong, Kansara, Maya, Thomas, David M., Smyth, Mark J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Landes Bioscience 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518504/
https://www.ncbi.nlm.nih.gov/pubmed/23243595
http://dx.doi.org/10.4161/onci.21680
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author Paget, Christophe
Duret, Helene
Ngiow, Shin Foong
Kansara, Maya
Thomas, David M.
Smyth, Mark J.
author_facet Paget, Christophe
Duret, Helene
Ngiow, Shin Foong
Kansara, Maya
Thomas, David M.
Smyth, Mark J.
author_sort Paget, Christophe
collection PubMed
description Recent evidence demonstrates that the efficacy of conventional anticancer therapies including chemotherapy requires a functional immune system. Here, we addressed the possibility that the antitumor effect of a selective Smoothened antagonist and Hedgehog (Hh) pathway inhibitor (LDE225), a promising anticancer drug, might at least partially depend on the immune system. To this aim, we used tumor cell lines derived from a murine model of radiation-induced osteosarcoma. In vitro treatment of osteosarcoma cells with LDE225 resulted in a decreased ability of tumor cells to proliferate, but had no effect on their viability. Flow cytometry analysis demonstrated that LDE225-treatment did not detectably modulate the immunogenicity of tumor cells. Moreover, LDE225 did not display any pro-apoptotic properties on osteosarcoma cells, highlighting that its antitumor profile mainly derives from a cytostatic effect. Furthermore, calreticulin exposure, a key feature of immunogenic cell death, was not provoked by LDE225, neither alone nor combined with recognized immunogenic drugs. Finally, the oral administration of LDE225 to osteosarcoma-bearing mice did significantly delay the tumor growth even in an immunocompromised setting. These data suggest that inhibiting Hh signaling can control osteosarcoma cell proliferation but does not modulate the immunogenic profile of these cells.
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spelling pubmed-35185042012-12-14 Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma Paget, Christophe Duret, Helene Ngiow, Shin Foong Kansara, Maya Thomas, David M. Smyth, Mark J. Oncoimmunology Research Paper Recent evidence demonstrates that the efficacy of conventional anticancer therapies including chemotherapy requires a functional immune system. Here, we addressed the possibility that the antitumor effect of a selective Smoothened antagonist and Hedgehog (Hh) pathway inhibitor (LDE225), a promising anticancer drug, might at least partially depend on the immune system. To this aim, we used tumor cell lines derived from a murine model of radiation-induced osteosarcoma. In vitro treatment of osteosarcoma cells with LDE225 resulted in a decreased ability of tumor cells to proliferate, but had no effect on their viability. Flow cytometry analysis demonstrated that LDE225-treatment did not detectably modulate the immunogenicity of tumor cells. Moreover, LDE225 did not display any pro-apoptotic properties on osteosarcoma cells, highlighting that its antitumor profile mainly derives from a cytostatic effect. Furthermore, calreticulin exposure, a key feature of immunogenic cell death, was not provoked by LDE225, neither alone nor combined with recognized immunogenic drugs. Finally, the oral administration of LDE225 to osteosarcoma-bearing mice did significantly delay the tumor growth even in an immunocompromised setting. These data suggest that inhibiting Hh signaling can control osteosarcoma cell proliferation but does not modulate the immunogenic profile of these cells. Landes Bioscience 2012-11-01 /pmc/articles/PMC3518504/ /pubmed/23243595 http://dx.doi.org/10.4161/onci.21680 Text en Copyright © 2012 Landes Bioscience http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Research Paper
Paget, Christophe
Duret, Helene
Ngiow, Shin Foong
Kansara, Maya
Thomas, David M.
Smyth, Mark J.
Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma
title Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma
title_full Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma
title_fullStr Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma
title_full_unstemmed Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma
title_short Studying the role of the immune system on the antitumor activity of a Hedgehog inhibitor against murine osteosarcoma
title_sort studying the role of the immune system on the antitumor activity of a hedgehog inhibitor against murine osteosarcoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518504/
https://www.ncbi.nlm.nih.gov/pubmed/23243595
http://dx.doi.org/10.4161/onci.21680
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