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This study investigated the ability of fibroblasts to alter the response of non\u2010small cell lung cancer (NSCLC) cell lines to cisplatin exposure. A cytotoxicity assay was performed to determine the IC<jats:sub>50<\/jats:sub> of cisplatin using MTT. The assay was performed on NSCLC cell lines A549 and H1299 monocultures and co\u2010cultures with fibroblasts. The co\u2010culture was performed directly with the HSF cell line and indirectly through conditioned media. The ELISA technique was then used to determine the expression of biochemical markers at various time points of co\u2010culture before and after cisplatin exposure. We observed a time\u2010dependent evolution in the fibroblast\u2010cancer cell interplay. Initially, fibroblast co\u2010culture enhanced the cytotoxic effect of cisplatin, as reflected by decreased IC<jats:sub>50<\/jats:sub> values after 24\u2009h of co\u2010culture. However, prolonged co\u2010culture durations (48\u201396\u2009h) led to the emergence of cisplatin resistance, coinciding with increased IC<jats:sub>50<\/jats:sub> values and altered expression of key biochemical markers. The findings suggest that fibroblasts undergo a potential identity switch over time, transitioning from a tumor\u2010restrictive to a tumor\u2010promoting phenotype. This switch was associated with the activation of EGFR and FGF signaling pathways, increased expression of angiogenic and metastasis markers (e.g., VEGF, MMP2 &amp; MMP9), and inhibition of apoptosis (e.g., reduced caspase expression). Our results suggest that fibroblasts may initially potentiate the effect of cisplatin on NSCLC cells; however, in a time\u2010dependent manner, fibroblast co\u2010culture attenuates the cytotoxic efficacy of cisplatin.<\/jats:p>","DOI":"10.1002\/jbt.70201","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T02:17:38Z","timestamp":1741745858000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cross\u2010Talk Signaling Between Non\u2010Small Cell Lung Cancer Cell Lines and Fibroblasts Attenuates the Cytotoxic Effect of Cisplatin"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7000-3967","authenticated-orcid":false,"given":"Nouran","family":"Ebid","sequence":"first","affiliation":[{"name":"Pharmacology &amp; Toxicology Department Faculty of Pharmacy, Egyptian Russian University Badr City 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