Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth
Purpose: The Epstein-Barr virus (EBV)-associated cancer nasopharyngeal carcinoma (NPC) is rare in Europe and North America but is a real public health problem in some regions of the world, such as southern Asia, North Africa, and for Inuit populations. Due to the anatomy and location of the nasophar...
Published in: | Drug Design, Development and Therapy |
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Online Access: | http://prodinra.inra.fr/ft/9292D599-B2FF-40A2-8D6A-B2C01A8D7BE4 http://prodinra.inra.fr/record/453328 https://doi.org/10.2147/DDDT.S172538 |
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ftinraparis:oai:prodinra.inra.fr:453328 2023-05-15T16:55:14+02:00 Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth Gallardo, Franck Mariamé, Bernard Gence, Remi Tilkin-Mariamé, Anne-Francoise 2018 application/pdf http://prodinra.inra.fr/ft/9292D599-B2FF-40A2-8D6A-B2C01A8D7BE4 http://prodinra.inra.fr/record/453328 https://doi.org/10.2147/DDDT.S172538 eng eng https://creativecommons.org/licenses/by-nc/3.0/ CC-BY-NC Drug Design, Development and Therapy (12), 2805-2814. (2018) ARTICLE 2018 ftinraparis https://doi.org/10.2147/DDDT.S172538 2018-12-18T23:25:35Z Purpose: The Epstein-Barr virus (EBV)-associated cancer nasopharyngeal carcinoma (NPC) is rare in Europe and North America but is a real public health problem in some regions of the world, such as southern Asia, North Africa, and for Inuit populations. Due to the anatomy and location of the nasopharynx, surgery is rarely used to treat primary NPC cancers. Treatment by radiotherapy, combined or not with chemotherapy, are efficient for primary tumors but often do not protect against fatal relapses or metastases. Methods: Search for new therapeutic molecules through high content screening lead to the identification of Ivermectin (IVM) as a promising drug. IVM is a US Food and Drug Administration-approved macrocyclic lactone widely used as anthelmintic and insecticidal agent that has also shown protective effects against cancers. Results: We show here that IVM has cytotoxic activity in vitro against NPC cells, in which it reduces MAPKs pathway activation through the inhibition PAK-1 activity. Moreover, all macrocyclic lactones tested and a PAK1 inhibitor are cytotoxic in vitro for EBV-positive and EBV-negative NPC tumor cells. We have also shown that IVM intraperitoneal repeated injections, at US Food and Drug Administration-approved doses, have no significant toxicity and decrease NPC subcutaneous tumors development in nude mice. Conclusion: Macrocyclic lactones appear as promising molecules against NPC targeting PAK-1 with no detectable adverse effect. Article in Journal/Newspaper inuit Institut National de la Recherche Agronomique: ProdINRA Drug Design, Development and Therapy Volume 12 2805 2814 |
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Open Polar |
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Institut National de la Recherche Agronomique: ProdINRA |
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ftinraparis |
language |
English |
description |
Purpose: The Epstein-Barr virus (EBV)-associated cancer nasopharyngeal carcinoma (NPC) is rare in Europe and North America but is a real public health problem in some regions of the world, such as southern Asia, North Africa, and for Inuit populations. Due to the anatomy and location of the nasopharynx, surgery is rarely used to treat primary NPC cancers. Treatment by radiotherapy, combined or not with chemotherapy, are efficient for primary tumors but often do not protect against fatal relapses or metastases. Methods: Search for new therapeutic molecules through high content screening lead to the identification of Ivermectin (IVM) as a promising drug. IVM is a US Food and Drug Administration-approved macrocyclic lactone widely used as anthelmintic and insecticidal agent that has also shown protective effects against cancers. Results: We show here that IVM has cytotoxic activity in vitro against NPC cells, in which it reduces MAPKs pathway activation through the inhibition PAK-1 activity. Moreover, all macrocyclic lactones tested and a PAK1 inhibitor are cytotoxic in vitro for EBV-positive and EBV-negative NPC tumor cells. We have also shown that IVM intraperitoneal repeated injections, at US Food and Drug Administration-approved doses, have no significant toxicity and decrease NPC subcutaneous tumors development in nude mice. Conclusion: Macrocyclic lactones appear as promising molecules against NPC targeting PAK-1 with no detectable adverse effect. |
format |
Article in Journal/Newspaper |
author |
Gallardo, Franck Mariamé, Bernard Gence, Remi Tilkin-Mariamé, Anne-Francoise |
spellingShingle |
Gallardo, Franck Mariamé, Bernard Gence, Remi Tilkin-Mariamé, Anne-Francoise Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth |
author_facet |
Gallardo, Franck Mariamé, Bernard Gence, Remi Tilkin-Mariamé, Anne-Francoise |
author_sort |
Gallardo, Franck |
title |
Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth |
title_short |
Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth |
title_full |
Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth |
title_fullStr |
Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth |
title_full_unstemmed |
Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth |
title_sort |
macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through pak1 inhibition and reduce in vivo tumor growth |
publishDate |
2018 |
url |
http://prodinra.inra.fr/ft/9292D599-B2FF-40A2-8D6A-B2C01A8D7BE4 http://prodinra.inra.fr/record/453328 https://doi.org/10.2147/DDDT.S172538 |
genre |
inuit |
genre_facet |
inuit |
op_source |
Drug Design, Development and Therapy (12), 2805-2814. (2018) |
op_rights |
https://creativecommons.org/licenses/by-nc/3.0/ |
op_rightsnorm |
CC-BY-NC |
op_doi |
https://doi.org/10.2147/DDDT.S172538 |
container_title |
Drug Design, Development and Therapy |
container_volume |
Volume 12 |
container_start_page |
2805 |
op_container_end_page |
2814 |
_version_ |
1766046210925264896 |