Coralyne enhances radiosensitivity of A549 cells by suppressing radiation-induced pro-survival transcriptional programs

Radioresistance remains a major cause of radiotherapy failure in non-small cell lung cancer (NSCLC), driven in part by rapid activation of pro-survival transcriptional programs following ionising radiation (IR). Targeting this adaptive response represents a promising strategy for radiosensitisation. Here, we show that coralyne, a synthetic protoberberine isoquinoline alkaloid, enhances A549 cell radiosensitivity by suppressing radiation-induced transcriptional reprogramming. Coralyne interacts with DNA and is associated with alterations in radiation-responsive transcriptional programs. Clonogenic survival analyses demonstrated concentration-dependent radiosensitisation, with the strongest effect observed at 25 μM coralyne. Whole-transcriptome profiling further revealed coordinated radiation-induced changes in the expression of genes associated with MAPK, EGFR, Ras and Wnt signalling pathways, whereas coralyne substantially altered these transcriptional responses. Functionally, coralyne enhanced the accumulation and prolonged persistence of radiation-induced γH2AX signals, accompanied by increased micronucleus formation, mitochondrial dysfunction, elevated reactive oxygen species and enhanced caspase-3-dependent apoptosis. Importantly, these radiosensitising effects were substantially weaker in non-malignant BEAS-2B lung epithelial cells, indicating differential responses between A549 and BEAS-2B cells. Electrophoretic and HRM-PCR analyses confirmed direct interaction of coralyne with DNA, suggesting that DNA interaction may contribute to the observed cellular responses. Collectively, our findings suggest that coralyne enhances radiosensitivity in A549 cells and is associated with modulation of radiation-induced pro-survival transcriptional programs, prolonged persistence of DNA damage markers and activation of mitochondrial apoptotic pathways. These results demonstrate the radiosensitising activity of coralyne in A549 cells and support further investigation of coralyne-based combination strategies for overcoming tumour radioresistance.