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

Autor: 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
Přispěvatelé: Centre Scientifique de Monaco (CSM), Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Hôpital Pasteur [Nice] (CHU), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire Génomique, bioinformatique et chimie moléculaire (GBCM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Puybonnieux, Aurélie, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Cell Survival
Antineoplastic Agents
Apoptosis
[SDV.CAN]Life Sciences [q-bio]/Cancer
Review
urologic and male genital diseases
Receptors
Interleukin-8B
Receptors
Interleukin-8A
Inhibitory Concentration 50
Mice
angiogenesis
Head and Neck Squamous Cell Carcinoma
[SDV.CAN] Life Sciences [q-bio]/Cancer
Cell Movement
Cell Line
Tumor
Animals
Humans
ELR+CXCL cytokines
CXCR1/2 inhibitor
neoplasms
Cell Proliferation
Clear cell Renal Cell Carcinoma
Prognosis
ELR + CXCL cytokines
Xenograft Model Antitumor Assays
Kidney Neoplasms
female genital diseases and pregnancy complications
Molecular Docking Simulation
stomatognathic diseases
Head and Neck Neoplasms
[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Signal Transduction
Zdroj: Theranostics
Theranostics, Ivyspring International Publisher, 2019, 9 (18), pp.5332-5346. ⟨10.7150/thno.34681⟩
Theranostics, 2019, 9 (18), pp.5332-5346. ⟨10.7150/thno.34681⟩
ISSN: 1838-7640
DOI: 10.7150/thno.34681⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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