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New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments

Clear cell Renal Cell (RCC) and Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by a pro-angiogenic/pro-inflammatory context. Despite conventional or targeted therapies, metastatic RCC and HNSCC remain incurable. Alternative treatments to reference therapies (sunitinib, a multi tyro...

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Autores principales: Dufies, Maeva, Grytsai, Oleksandr, Ronco, Cyril, Camara, Oumar, Ambrosetti, Damien, Hagege, Anaïs, Parola, Julien, Mateo, Lou, Ayrault, Marion, Giuliano, Sandy, Grépin, Renaud, Lagarde, Nathalie, Montes, Matthieu, Auberger, Patrick, Demange, Luc, Benhida, Rachid, Pagès, Gilles
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691587/
https://www.ncbi.nlm.nih.gov/pubmed/31410218
http://dx.doi.org/10.7150/thno.34681
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author Dufies, Maeva
Grytsai, Oleksandr
Ronco, Cyril
Camara, Oumar
Ambrosetti, Damien
Hagege, Anaïs
Parola, Julien
Mateo, Lou
Ayrault, Marion
Giuliano, Sandy
Grépin, Renaud
Lagarde, Nathalie
Montes, Matthieu
Auberger, Patrick
Demange, Luc
Benhida, Rachid
Pagès, Gilles
author_facet Dufies, Maeva
Grytsai, Oleksandr
Ronco, Cyril
Camara, Oumar
Ambrosetti, Damien
Hagege, Anaïs
Parola, Julien
Mateo, Lou
Ayrault, Marion
Giuliano, Sandy
Grépin, Renaud
Lagarde, Nathalie
Montes, Matthieu
Auberger, Patrick
Demange, Luc
Benhida, Rachid
Pagès, Gilles
author_sort Dufies, Maeva
collection PubMed
description Clear cell Renal Cell (RCC) and Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by a pro-angiogenic/pro-inflammatory context. Despite conventional or targeted therapies, metastatic RCC and HNSCC remain incurable. Alternative treatments to reference therapies (sunitinib, a multi tyrosine kinase inhibitor for RCC or cisplatin for HNSCC) are urgently needed on relapse. Here, we described the relevance of targeting the ELR+CXCL cytokines receptors, CXCR1/2, for the treatment of these two cancer types. Methods: The relevance to patient treatment was evaluated by correlating the ELR(+)CXCL/CXCR1/2 levels to survival using online available data. We report herein the synthesis of new pharmacological inhibitors of CXCR1/2 with anti-proliferation/survival activity. The latter was evaluated with the XTT assay with leukemic, breast, RCC and HNSCC cell lines. Their relevance as an alternative treatment was tested on sunitinib- and cisplatin- resistant cells. The most efficient compound was then tested in a mouse model of RCC and HNSCC. Results: RCC and HNSCC expressed the highest amounts of CXCR1/2 of all cancers. High levels of ELR(+)CXCL cytokines (CXCL1, 2, 3, 5, 6, 7, 8) correlated to shorter survival. Among the 33 synthesized and tested molecules, compound C29 reduced ELR(+)CXCL/CXCR1/2-dependent proliferation and migration of endothelial cells. C29 exerted an anti-proliferation/survival activity on a panel of cancer cells including naive and resistant RCC and HNSCC cells. C29 reduced the growth of experimental RCC and HNSCC tumors by decreasing tumor cell proliferation, angiogenesis and ELR(+)/CXCL-mediated inflammation. Conclusion: Our study highlights the relevance of new CXCR1/2 inhibitors for the treatment of RCC or HNSCC as first-line treatment or at relapse on reference therapies.
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spelling pubmed-66915872019-08-13 New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments Dufies, Maeva Grytsai, Oleksandr Ronco, Cyril Camara, Oumar Ambrosetti, Damien Hagege, Anaïs Parola, Julien Mateo, Lou Ayrault, Marion Giuliano, Sandy Grépin, Renaud Lagarde, Nathalie Montes, Matthieu Auberger, Patrick Demange, Luc Benhida, Rachid Pagès, Gilles Theranostics Review Clear cell Renal Cell (RCC) and Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by a pro-angiogenic/pro-inflammatory context. Despite conventional or targeted therapies, metastatic RCC and HNSCC remain incurable. Alternative treatments to reference therapies (sunitinib, a multi tyrosine kinase inhibitor for RCC or cisplatin for HNSCC) are urgently needed on relapse. Here, we described the relevance of targeting the ELR+CXCL cytokines receptors, CXCR1/2, for the treatment of these two cancer types. Methods: The relevance to patient treatment was evaluated by correlating the ELR(+)CXCL/CXCR1/2 levels to survival using online available data. We report herein the synthesis of new pharmacological inhibitors of CXCR1/2 with anti-proliferation/survival activity. The latter was evaluated with the XTT assay with leukemic, breast, RCC and HNSCC cell lines. Their relevance as an alternative treatment was tested on sunitinib- and cisplatin- resistant cells. The most efficient compound was then tested in a mouse model of RCC and HNSCC. Results: RCC and HNSCC expressed the highest amounts of CXCR1/2 of all cancers. High levels of ELR(+)CXCL cytokines (CXCL1, 2, 3, 5, 6, 7, 8) correlated to shorter survival. Among the 33 synthesized and tested molecules, compound C29 reduced ELR(+)CXCL/CXCR1/2-dependent proliferation and migration of endothelial cells. C29 exerted an anti-proliferation/survival activity on a panel of cancer cells including naive and resistant RCC and HNSCC cells. C29 reduced the growth of experimental RCC and HNSCC tumors by decreasing tumor cell proliferation, angiogenesis and ELR(+)/CXCL-mediated inflammation. Conclusion: Our study highlights the relevance of new CXCR1/2 inhibitors for the treatment of RCC or HNSCC as first-line treatment or at relapse on reference therapies. Ivyspring International Publisher 2019-07-09 /pmc/articles/PMC6691587/ /pubmed/31410218 http://dx.doi.org/10.7150/thno.34681 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Review
Dufies, Maeva
Grytsai, Oleksandr
Ronco, Cyril
Camara, Oumar
Ambrosetti, Damien
Hagege, Anaïs
Parola, Julien
Mateo, Lou
Ayrault, Marion
Giuliano, Sandy
Grépin, Renaud
Lagarde, Nathalie
Montes, Matthieu
Auberger, Patrick
Demange, Luc
Benhida, Rachid
Pagès, Gilles
New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments
title New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments
title_full New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments
title_fullStr New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments
title_full_unstemmed New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments
title_short New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments
title_sort new cxcr1/cxcr2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691587/
https://www.ncbi.nlm.nih.gov/pubmed/31410218
http://dx.doi.org/10.7150/thno.34681
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