Targeting CCR3 with antagonist SB 328437 sensitizes 5‑fluorouracil‑resistant gastric cancer cells: Experimental evidence and computational insights

Gutiérrez,Álvaro; Reyes,María Elena; Larronde,Carolina; Brebi,Priscilla; Mora‑Lagos,Bárbara

doi:10.3892/ol.2024.14429

Targeting CCR3 with antagonist SB 328437 sensitizes 5‑fluorouracil‑resistant gastric cancer cells: Experimental evidence and computational insights

Authors:
- Álvaro Gutiérrez
- María Elena Reyes
- Carolina Larronde
- Priscilla Brebi
- Bárbara Mora‑Lagos
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Affiliations: Laboratory of Integrative Biology, Centro de Excelencia en Medicina Traslacional, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, 4810296 Temuco, Chile, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, 4810101 Temuco, Chile
Published online on: May 1, 2024 https://doi.org/10.3892/ol.2024.14429
Article Number: 296

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Abstract

Gastric cancer (GC) ranks fifth globally in cancer diagnoses and third for cancer‑related deaths. Chemotherapy with 5‑fluorouracil (5‑FU), a primary treatment, faces challenges due to the development of chemoresistance. Tumor microenvironment factors, including C‑C motif chemokine receptor 3 (CCR3), can contribute to chemoresistance. The present study evaluated the effect of CCR3 receptor inhibition using the antagonist SB 328437 and the molecular dynamics of this interaction on resistance to 5‑FU in gastric cancer cells. The 5‑FU‑resistant AGS cell line (AGS R‑5FU) demonstrated notable tolerance to higher concentrations of 5‑FU, with a 2.6‑fold increase compared with the parental AGS cell line. Furthermore, the mRNA expression levels of thymidylate synthase (TS), a molecular marker for 5‑FU resistance, were significantly elevated in AGS R‑5FU cells. CCR3 was shown to be expressed at significantly higher levels in these resistant cells. Combining SB 328437 with 5‑FU resulted in a significant decrease in cell viability, particularly at higher concentrations of 5‑FU. Furthermore, when SB 328437 was combined with 5‑FU at a high concentration, the relative mRNA expression levels of CCR3 and TS decreased significantly. Computational analysis of CCR3 demonstrated dynamic conformational changes, especially in extracellular loop 2 region, which indicated potential alterations in ligand recognition. Docking simulations demonstrated that SB 328437 bound to the allosteric site of CCR3, inducing a conformational change in ECL2 and hindering ligand recognition. The present study provides comprehensive information on the molecular and structural aspects of 5‑FU resistance and CCR3 modulation, highlighting the potential for therapeutic application of SB 328437 in GC treatment.

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