Molecular Mechanisms Underlying Sequence-Dependent Cytotoxicity of Cisplatin-Pemetrexed Therapy in A549 and BEAS-2B Cells

Akman G., Özcan F. G.

BRAZILIAN ARCHIVES OF BIOLOGY AND TECHNOLOGY, cilt.69, 2026 (SCI-Expanded, Scopus)

Özet

Lung cancer continues to be a major contributor to cancer-related deaths globally. Antifolate agents and platinum-based medications form the basis of chemotherapy treatments. This study examined the distinct effects of pemetrexed disodium and cisplatin, both separately and sequentially, on cell cycle regulation in immortalized bronchial epithelial (BEAS-2B) and lung cancer (A549) cell lines. The MTT assay was used to measure cytotoxicity, and caspase-3,-7, and-9 activities were used to measure apoptotic activation. Quantitative real-time PCR (qRT-PCR) was used to analyze cell cycle gene expression profiles. Critically, while the sequential Cisplatin -> Pemetrexed regimen maintained potent efficacy against A549 cells, it exhibited a distinct protective antagonistic interaction (CI>10) in non-malignant BEAS-2B cells, significantly mitigating cytotoxicity compared to cisplatin monotherapy. This treatment strategy significantly increased caspase-3,-7, and-9 activation in A549 cells. Gene expression analysis revealed downregulation of most cyclins, cyclin-dependent kinases, and DNA repair genes in A549 cells, whereas these genes were upregulated in BEAS-2B cells. These findings demonstrate preferential cytotoxicity toward lung cancer cells compared to immortalized bronchial epithelial cells, providing a molecular basis for optimizing combination chemotherapy strategies.