@Article{or.2025.069408,
AUTHOR = {Muhammad Noman Khan, Kang Tian, John R. Gordon, Fang Li, Song-Ze Ding},
TITLE = {CXCR1 and CXCR2 Antagonism with G31P Attenuates Chemotherapy-Induced Lung Inflammation and Augments the Gefitinib Therapeutic Response in Lung Cancer},
JOURNAL = {Oncology Research},
VOLUME = {33},
YEAR = {2025},
NUMBER = {12},
PAGES = {3837--3854},
URL = {http://www.techscience.com/or/v33n12/64641},
ISSN = {1555-3906},
ABSTRACT = { <b>Objectives:</b> Chemotherapy-induced lung inflammation limits the efficacy of anticancer therapies such as gefitinib in non-small cell lung cancer (NSCLC). Glutamic acid-leucine-arginine positive (ELR+) CXC chemokines and their receptors, CXC chemokine receptor 1 and 2 (CXCR1 and CXCR2), mediate both inflammatory responses and tumor progression. This study evaluated the effects of CXCR1/2 antagonism by G31P, a CXC motif chemokine ligand 8 (CXCL8)-mutated peptide, alone or in combination with gefitinib, on lung cancer growth and chemotherapy-induced pulmonary inflammation. <b>Methods:</b> Human NSCLC cell lines (A549 and H460) were treated with gefitinib and/or G31P. Cell proliferation, apoptosis, and signaling pathways, including protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation, were evaluated by cell counting kit-8 (CCK-8) assay, flow cytometry, and Western blotting. An orthotopic lung tumor xenograft model was established in BALB/c nude mice to evaluate tumor growth, metastasis, cytokine expression, and lung histopathology. A bleomycin-induced lung injury model was also used to assess the anti-inflammatory effects of G31P, with or without gefitinib, by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry of inflammatory markers. <b>Results:</b> G31P and Gefitinib, either alone or combined, inhibited proliferation and migration of A549 and H460 cells <i>in vitro</i>. Combination treatment effectively reduced AKT and ERK phosphorylation in both cell lines. <i>In vivo</i>, G31P with gefitinib significantly suppressed tumor growth, metastasis, and increased apoptosis. G31P decreased CXCL1 and CXCL2, and tumor necrosis factor-alpha (TNF-α) mRNA levels, lung hydroxyproline content, and myeloperoxidase (MPO) activity in the lungs of mice. In the bleomycin-induced lung injury model, G31P similarly reduced inflammatory responses. <b>Conclusion:</b> CXCR1/2 antagonism by G31P attenuates chemotherapy-induced pulmonary inflammation and enhances the anti-tumor efficacy of gefitinib in NSCLC. These findings support the therapeutic potential of G31P as an adjuvant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to improve clinical outcomes by limiting inflammation.},
DOI = {10.32604/or.2025.069408}
}