Nitroxoline Enhances Radiosensitivity in Non-Small Cell Lung Cancer by Suppressing STAT3-AKT-MTOR Survival Signaling

Radiotherapy is the central component in non-small cell lung cancer (NSCLC) treatment. Nonetheless, its therapeutic effectiveness is frequently compromised by adaptive engagement of prosurvival signaling pathways that foster radioresistance. STAT3 functions as the central signaling node that orchestrates cellular survival responses following radiation exposure. This study investigated whether nitroxoline, a clinically approved antimicrobial agent with STAT3-inhibitory activity, enhances radiosensitivity of NSCLC cells and how these effects are mechanistically regulated. We examined the combined effects of nitroxoline and radiation on cell viability and associated signaling pathways in NSCLC cells. Nitroxoline significantly enhanced radiation-induced cytotoxicity and suppressed clonogenic survival compared with radiation alone. Irradiation increased STAT3, AKT, and mTOR phosphorylation, whereas nitroxoline effectively suppressed the basal and radiation-induced activation of these pathways. The combination treatment markedly augmented radiation-induced apoptosis, as demonstrated by increased p53 expression and enhanced PARP and caspase-3 cleavage. Additionally, nitroxoline amplified radiation-induced DNA damage signaling, resulting in pronounced γ-H2AX and DNA-PKcs accumulation. Nitroxoline enhanced NSCLC cell radiosensitivity by suppressing STAT3-AKT-mTOR survival signaling, promoting apoptosis, and amplifying radiation-induced DNA damage, indicating the potential of repurposing nitroxoline as a radiosensitizer to improve radiotherapy outcomes in patients with NSCLC.