A Potent Solution for Tumor Growth and Angiogenesis Suppression Via an ELRCXCL-CXCR1/2 Pathway Inhibitor

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Jun 19

PMID 38894897

Authors

Oleksandr Grytsai

Maeva Dufies

Julie Le Du

Olivia Rastoin

Leticia Christina Pires Goncalves

Lou Mateo

Sandra Lacas-Gervais

Yihai Cao

Luc Demange

Gilles Pages

Rachid Benhida

Cyril Ronco

Affiliations

Soon will be listed here.

Abstract

CXCR1/2 biomolecules play vital roles in cancer cell proliferation, tumor inflammation, and angiogenesis, making them attractive drug targets. In clear cell renal cell carcinoma (RCC) and head and neck squamous cell carcinoma (HNSCC), where CXCR1/2 is overexpressed, inhibition studies are limited. Building upon previous research efforts, we investigated new ,'-diarylurea analogues as ELRCXCL-CXCR1/2 inhibitors. Evaluations on RCC and HNSCC cell lines and 3D spheroid cultures identified compound as a lead molecule, exhibiting significant inhibition of invasion, migration, and neo-angiogenesis. It demonstrated strong interference with the signaling pathway, with high selectivity toward kinases. studies on zebrafish embryos and RCC xenografted mice showed notable anticancer, antimetastatic, and antiangiogenic effects after oral administration and minimal toxicity. Compound emerges as a promising candidate for further preclinical development as an oral anticancer and antiangiogenic drug targeting the ELRCXCL-CXCR1/2 pathway.

References

Ndiaye P, Dufies M, Giuliano S, Douguet L, Grepin R, Durivault J . VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness. Theranostics. 2019; 9(3):661-675. PMC: 6376471. DOI: 10.7150/thno.27794. View

Wang J, Hu W, Wang K, Yu J, Luo B, Luo G . Repertaxin, an inhibitor of the chemokine receptors CXCR1 and CXCR2, inhibits malignant behavior of human gastric cancer MKN45 cells in vitro and in vivo and enhances efficacy of 5-fluorouracil. Int J Oncol. 2016; 48(4):1341-52. PMC: 4777600. DOI: 10.3892/ijo.2016.3371. View

Goel B, Tiwari A, Pandey R, Singh A, Kumar S, Sinha A . Therapeutic approaches for the treatment of head and neck squamous cell carcinoma-An update on clinical trials. Transl Oncol. 2022; 21:101426. PMC: 9046875. DOI: 10.1016/j.tranon.2022.101426. View

Tran T, Kinch L, Pena-Llopis S, Kockel L, Grishin N, Jiang H . Platelet-derived growth factor/vascular endothelial growth factor receptor inactivation by sunitinib results in Tsc1/Tsc2-dependent inhibition of TORC1. Mol Cell Biol. 2013; 33(19):3762-79. PMC: 3811881. DOI: 10.1128/MCB.01570-12. View

Greene S, Robbins Y, Mydlarz W, Huynh A, Schmitt N, Friedman J . Inhibition of MDSC Trafficking with SX-682, a CXCR1/2 Inhibitor, Enhances NK-Cell Immunotherapy in Head and Neck Cancer Models. Clin Cancer Res. 2019; 26(6):1420-1431. PMC: 7073293. DOI: 10.1158/1078-0432.CCR-19-2625. View

Tlemsani C, Huillard O, Arrondeau J, Boudou-Rouquette P, Cessot A, Blanchet B . Effect of glucuronidation on transport and tissue accumulation of tyrosine kinase inhibitors: consequences for the clinical management of sorafenib and regorafenib. Expert Opin Drug Metab Toxicol. 2015; 11(5):785-94. DOI: 10.1517/17425255.2015.1030392. View

Dufies M, Grytsai O, Ronco C, Camara O, Ambrosetti D, Hagege A . New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments. Theranostics. 2019; 9(18):5332-5346. PMC: 6691587. DOI: 10.7150/thno.34681. View

Grepin R, Guyot M, Jacquin M, Durivault J, Chamorey E, Sudaka A . Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines. Oncogene. 2011; 31(13):1683-94. DOI: 10.1038/onc.2011.360. View

Che J, Song R, Chen B, Dong X . Targeting CXCR1/2: The medicinal potential as cancer immunotherapy agents, antagonists research highlights and challenges ahead. Eur J Med Chem. 2019; 185:111853. DOI: 10.1016/j.ejmech.2019.111853. View

10.

Hagege A, Saada-Bouzid E, Ambrosetti D, Rastoin O, Boyer J, He X . Targeting of c-MET and AXL by cabozantinib is a potential therapeutic strategy for patients with head and neck cell carcinoma. Cell Rep Med. 2022; 3(9):100659. PMC: 9512663. DOI: 10.1016/j.xcrm.2022.100659. View

11.

Sitaru S, Budke A, Bertini R, Sperandio M . Therapeutic inhibition of CXCR1/2: where do we stand?. Intern Emerg Med. 2023; 18(6):1647-1664. PMC: 10227827. DOI: 10.1007/s11739-023-03309-5. View

12.

Lee B, Jang J, Seo C, Kim C . Crosstalk between head and neck cancer cells and lymphatic endothelial cells promotes tumor metastasis via CXCL5-CXCR2 signaling. FASEB J. 2020; 35(1):e21181. DOI: 10.1096/fj.202001455R. View

13.

Mimeault M, Batra S . Emergence of zebrafish models in oncology for validating novel anticancer drug targets and nanomaterials. Drug Discov Today. 2012; 18(3-4):128-40. PMC: 3562372. DOI: 10.1016/j.drudis.2012.08.002. View

14.

David J, Dominguez C, Hamilton D, Palena C . The IL-8/IL-8R Axis: A Double Agent in Tumor Immune Resistance. Vaccines (Basel). 2016; 4(3). PMC: 5041016. DOI: 10.3390/vaccines4030022. View

15.

Horuk R . Chemokine receptor antagonists: overcoming developmental hurdles. Nat Rev Drug Discov. 2008; 8(1):23-33. DOI: 10.1038/nrd2734. View

16.

Varney M, Singh S, Li A, Mayer-Ezell R, Bond R, Singh R . Small molecule antagonists for CXCR2 and CXCR1 inhibit human colon cancer liver metastases. Cancer Lett. 2010; 300(2):180-8. PMC: 2994987. DOI: 10.1016/j.canlet.2010.10.004. View

17.

Montemagno C, Serrano B, Durivault J, Nataf V, Mocquot F, Amblard R . In vivo monitoring of the therapeutic efficacy of a CXCR1/2 inhibitor with 18F-FDG PET/CT imaging in experimental head and neck carcinoma: A feasibility study. Biochem Biophys Rep. 2021; 27:101098. PMC: 8374394. DOI: 10.1016/j.bbrep.2021.101098. View

18.

Cook K, Figg W . Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. 2010; 60(4):222-43. PMC: 2919227. DOI: 10.3322/caac.20075. View

19.

Ha H, Debnath B, Neamati N . Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases. Theranostics. 2017; 7(6):1543-1588. PMC: 5436513. DOI: 10.7150/thno.15625. View

20.

Pinto M, Owen G, Retamal I, Garrido M . Angiogenesis inhibitors in early development for gastric cancer. Expert Opin Investig Drugs. 2017; 26(9):1007-1017. DOI: 10.1080/13543784.2017.1361926. View