Synergistic Toxicity of Cold Gas Plasma and Cisplatin in Bladder Cancer Cells.

BACKGROUND/

objectivesBladder cancer remains a therapeutically challenging malignancy due to high recurrence rates, progression to muscle-invasive disease, and frequent resistance to cisplatin-based chemotherapy. Cold physical plasma (hereafter referred to as plasma) has emerged as a locally applicable modality that generates reactive oxygen species (ROS) and shows preclinical antitumor activity, offering a potential strategy to enhance cisplatin efficacy while enabling dose reduction. Here, we investigated combination treatment with cisplatin and argon plasma generated by the clinically approved kINPen jet in human bladder cancer models.

methodsThree bladder cancer cell lines representing distinct entities were used, namely the urothelial carcinoma lines RT-112 and T24, and the squamous cell carcinoma line SCaBER. IC

resultsPlasma and cisplatin exhibited opposing monotherapy sensitivity profiles across cell lines, creating a favorable basis for combination treatment. CDI analysis revealed clear synergy in SCaBER at intermediate cisplatin concentrations, additive effects in RT-112, and additive to mildly synergistic effects in T24. ROS profiling and scavenger experiments identified hydrogen peroxide as a key mediator of plasma and plasma-cisplatin cytotoxicity in SCaBER. In the TUM-CAM model, plasma and cisplatin monotherapies showed notable antitumoral potential. At the same time, plasma-cisplatin combination therapy elicited only modest effects on tumor growth and vascularization compared to monotreatments but induced distinct, cell line-specific alterations in cytokine and marker expression.

conclusionsThese findings demonstrate that plasma can potentiate cisplatin cytotoxicity in bladder cancer cells and reshape tumor-associated molecular signatures, supporting further optimization and preclinical evaluation of plasma-cisplatin combination therapy.