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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
Abstract : 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.
Cited literature [43 references]
https://hal-cnam.archives-ouvertes.fr/hal-02308756
Contributor : Aurélie Puybonnieux <>
Submitted on : Tuesday, October 8, 2019 - 4:56:21 PM
Last modification on : Friday, March 27, 2020 - 2:30:59 AM
Contributor : Aurélie Puybonnieux <>
Submitted on : Tuesday, October 8, 2019 - 4:56:21 PM
Last modification on : Friday, March 27, 2020 - 2:30:59 AM
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