Co-treatment of Colchicine and Rosiglitazone synergistically inhibits cytokine-driven inflammation and modulates the related hsa-miRNA26a-5p, hsa-miRNA21-5p, and STAT3 expression in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, and tumors harboring p53 mutations have limited therapeutic options. Chronic inflammation and microRNA dysregulation are key drivers of NSCLC progression, yet their coordinated therapeutic targeting remains poorly understood. This study aimed to evaluate whether a novel therapeutic combination of colchicine (Col) and rosiglitazone (Rosi) can modulate hsa-miRNA-26a-5p and hsa-miRNA-21-5p and influence IL-6/STAT3/axis-driven oncogenic signaling in NSCLC, particularly under inflammatory conditions. Given the central role of p53 gene in controlling cellular response to therapy, we investigated the role of mutant p53 vs wild-type in response to the individual and combined treatment of Col/Rosi in two NSCLC cell lines, A549 (p53-wild-type) and NCI-H358 (p53-null, transfected with p53-R273H mutant), using WST-1 viability assays, caspase-3 and PARP1 assays, western blotting, and RT-qPCR analysis of key miRNAs. In silico modeling and transcriptomic data from lung adenocarcinoma patients were used to support mechanistic and clinical relevance. In p53-R273H-mutant NCI-H358 cells, the Col/Rosi treatment synergistically reduced viability and induced apoptosis more effectively than either agent alone. This effect was associated with upregulation of the tumor-suppressor hsa-miRNA-26a-5p, suppression of oncogenic hsa-miRNA-21-5p, restoration of PTEN, PDCD4, and LIN28B, and inhibition of the IL-6/STAT3/NF-κB axis, consistent with patient-derived datasets. In contrast, p53-wild-type A549 cells exhibited an antagonistic response. This study identifies a genotype-dependent therapeutic interaction between Col and Rosi and demonstrates that reprogramming of hsa-miRNA-26a-5p and hsa-miRNA-21-5p constitutes a central mechanism underlying their anti-tumor and anti-inflammatory effects in NSCLC, particularly in p53-R273H-mutant NCI-H358 cells compared with p53-wild-type cells. The findings highlight the need for further investigation into the Col/Rosi combination for inflammation-related lung cancer and p53 expression. In vitro studies and bioinformatics analyses suggest a miRNA-associated regulatory mechanism that could guide future research.