Selective anti-CXCR2 receptor blockade by AZD5069 inhibits CXCL8-mediated pro-tumorigenic activity in human thyroid cancer cells in vitro

Sep 21, 2026

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Thyroid cancer is a prevalent endocrine malignancy, and a subset progresses despite current therapies. This study investigates whether targeting CXCR2 with the selective antagonist AZD5069 can modulate CXCL8-driven pro-tumorigenic effects in thyroid-cancer cells in vitro. Normal primary thyroid cells and multiple thyroid cancer cell lines were exposed to AZD5069, with effects assessed on proliferation, viability, CXCL8/CXCR2 gene expression, CXCL8 secretion, and cell migration. AZD5069 showed minimal impact on growth but reduced CXCR2 transcripts and, in key models, lowered CXCL8 secretion and migration.

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Journal of Endocrinological Investigation (2025) 48:53–65 [https://doi.org/10.1007/s40618-024-02410-6](https://doi.org/10.1007/s40618-024-02410-6) Selective anti‑CXCR2 receptor blockade by AZD5069 inhibits CXCL8‑mediated pro‑tumorigenic activity in human thyroid cancer cells in vitro F. Coperchini1 · A. Greco1 · E. Petrosino1 · L. Croce1,2 · M. Teliti1,2 · N. Marchesi3 · A. Pascale3 · B. Calì4 · P. Pignatti5 · F. Magri1,2 · M. Uddin6 · M. Rotondi1,2 Received: 30 April 2024 / Accepted: 6 June 2024 / Published online: 20 June 2024 © The Author(s) 2024 Abstract Background Thyroid cancer is the most common endocrine malignancy. Current therapies are successful, however some patients progress to therapeutically refractive disease. The immunotherapeutic potential of the CXCL8-chemokine/CXCR2-chemokine-receptor system is currently being explored in numerous human cancers. This study aimed to evaluate if the targeting of CXCR2 by its selective antagonist, AZD5069, could modulate CXCL8-mediated pro-tumorigenic effects in thyroid-cancer (TC) cells in vitro. Methods Normal human primary thyroid cells (NHT) and TC cell lines TPC-1 (RET/PTC), BCPAP, 8505C and 8305C (BRAFV600e) were treated with AZD5069 (100 pM-10 µM) over a time-course. Viability and proliferation were assessed by WST-1 and crystal violet assays. CXCL8 and CXCR2 mRNA were evaluated by RT-PCR. CXCL8-protein concentrations were measured in cell culture supernatants by ELISA. CXCR2 on cell surface was evaluated by flow-cytometry. Cellmigration was assessed by trans-well-migration chamber-system. Results AZD5069 exerted negligible effects on cell proliferation or viability. AZD5069 significantly reduced CXCR2,(but not CXCL8) mRNAs in all cell types. CXCR2 was reduced on the membrane of some TC cell lines. A significant reduction of the CXCL8 secretion was found in TPC-1 cells (basal-secretion) and NHT (TNFα-induced secretion) . AZD5069 significantly reduced basal and CXCL8-induced migration in NHT and different TC cells. Conclusions Our findings confirm the involvement of the CXCL8/CXCR2-axis in promoting pro-tumorigenic effects in TC cells, further demonstrating its immunotherapeutic significance in human cancer. Keywords AZD5069 · Thyroid cancer · CXCL8 · CXCR2 receptor * M. Rotondi [mario.rotondi@icsmaugeri.it](mario.rotondi@icsmaugeri.it) 1 Department of Internal Medicine and Therapeutics, University of Pavia, Via S. Maugeri 4, 27100 Pavia, Italy 2 Unit of Endocrinology and Metabolism, Laboratory for Endocrine Disruptors, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy 3 Unit of Pharmacology, Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy 4 Department of General and Minimally Invasive Surgery, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia (PV), Italy 5 Allergy and Immunology Unit, Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy 6 AstraZeneca Gothenburg, Biopharmaceuticals R&D, Mӧlndal, Sweden Abbreviations TC Thyroid cancer TSH Thyroid-stimulating hormone TM Tumor microenvironment TCM Thyroid cancer microenvironment CXCL8 Interleukin-8 CXCR1 C-X-C motif chemokine receptor 1 CXCR2 C-X-C motif chemokine receptor TANs Tumor-associated neutrophils mAb Monoclonal antibody DMEM Dulbecco’s Modified Eagle Medium FBS Fetal bovine serum MEM Minimum Essential Medium NHT Normal human thyroid cells TNF-α Tumor-necrosis-factor-α ANOVA Analysis of variance NS Not significant NETs Neutrophil extracellular traps Introduction Thyroid cancer (TC) is the endocrine cancer with the highest prevalence and incidence worldwide [1, 2], being papillary thyroid carcinoma the most frequent subtype in histology [3]. The incidence ofTC has markedly increased globally in recent years [1, 4], with an estimated new diagnosed cases of around 449,000 in women and 137,000 in men in 2020 [5] . The main strategies for effective treatment of TC include thyroidectomy, followed by radioiodi

FAQs

What is the main objective of the study?

To evaluate whether selective CXCR2 targeting with AZD5069 can modulate CXCL8-mediated pro-tumorigenic activity in thyroid-cancer cells in vitro.

Which experimental approaches were used to assess AZD5069 effects?

Cells were treated with AZD5069 across a time course, and viability/proliferation were measured with WST-1 and crystal violet; CXCL8 and CXCR2 mRNA were quantified by RT-PCR; CXCL8 secretion by ELISA; CXCR2 surface levels by flow cytometry; and migration by trans-well assays.

What were the key findings regarding proliferation and chemokine signaling?

AZD5069 had negligible effects on proliferation or viability, but significantly reduced CXCR2 mRNA across cell types; CXCR2 was reduced on the membrane in some cancer cell lines, and CXCL8 secretion and migration were reduced in specific models.

Sep 21, 2026

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