Dexamethasone enhances cold atmospheric-pressure plasma-induced antitumor effects in lung adenocarcinoma partly through ROS-associated apoptosis and suppression of PI3K/AKT signaling

Lung cancer remains a leading cause of cancer-related mortality, and the efficacy of conventional therapies is often limited by drug resistance and treatment-related toxicity. Cold atmospheric-pressure plasma (CAP) generates reactive oxygen and nitrogen species and has been shown to exert antitumor effects, but its potential synergy with clinically used drugs remains underexplored. In this study, CAP combined with dexamethasone (DEX) reduced the viability and impaired the migratory capacity of lung adenocarcinoma cells, with combination index analysis indicating synergism under most tested conditions. CAP plus DEX increased reactive oxygen species (ROS) accumulation and induced apoptosis, accompanied by changes in p53 and mitochondrial apoptosis-related proteins, as well as reduced PI3K/AKT-related protein expression. Rescue experiments with N-acetylcysteine (NAC) indicated that these antitumor effects were at least partly ROS-dependent. The combination reduced cell viability in multiple lung adenocarcinoma cell lines (A549, SPC-A1, and Calu-1) and inhibited tumor growth in a Calu-1 xenograft mouse model. Together, these results suggest that DEX enhances the antitumor activity of CAP under the experimental conditions used in this study, supporting CAP-DEX combination therapy as a potential strategy for lung adenocarcinoma.