期刊
THERANOSTICS
卷 9, 期 18, 页码 5332-5346出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.34681
关键词
ELR+CXCL cytokines; Clear cell Renal Cell Carcinoma; Head and Neck Squamous Cell Carcinoma; CXCR1/2 inhibitor; angiogenesis
资金
- CNRS, Universite Cote d'Azur
- Ministry of Higher Research and Education
- Canceropole PACA
- ANR
- INCA
- association Monegasque Cordons de Vie
- The Ligue Nationale contre le Cancer (Equipe Labellisee 2019)
- Fondation Francois Xavier Mora
- Government of the Principality of Monaco
- French Government through the UCAJEDI investments in the future project [ANR-15-IDEX-01]
- ANR TARMAC [ANR-17-CE17-0011-03]
- Region Provence Alpes Cote d'Azur (Project CONIAC)
- COST [CA15135]
- Conseil General 06
- FEDER
- Ministere de l'Enseignement Superieur
- Region Provence Alpes-Cote d'Azur
- INSERM
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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