Exploring the Cytotoxic Mechanisms and Anticancer Potentials of Silver Nanoparticles in Cisplatin-Sensitive and -Resistant Lung Adenocarcinoma: Insights from Proteomic and Mice Xenograft Studies

Silver nanoparticles (AgNPs) have shown great potential as therapeutic agents due to their ability to cause apoptotic cell death in cancer cells. However, little knowledge is available regarding the underlying action mechanisms of AgNPs towards multi-drug resistant cancer cells. Herein, we employed quantitative proteomics to investigate the cytotoxic mechanisms of AgNPs on both cisplatin-sensitive (A549 cells) and -resistant (A549/DDP cells) human lung adenocarcinoma and to explore their potential anticancer abilities. We first performed cytotoxicity tests and found that AgNPs exert similar cytotoxic effects on A549 and A549/DDP cells. At the proteome level, A549 and A549/DDP cells responded to AgNPs distinctively and similarly by causing cell apoptosis via upregulating RNA metabolism, suppressing VEGF siganling pathway, repressing p53-mediated pathways, promoting cell cycle arrest, etc. Additionally, AgNPs remarkably induced ROS generation in A549 and A549/DDP cells. The mitotoxicity results further confirmed the effectiveness of AgNPs in hampering mitochondrial function and respiration in A549 and A549/DDP cells. Overall, our investigations showed that AgNPs could effectively induce cell deaths in human lung adenocarcinoma cells regardless of their sensitivities to cisplatin, suggesting that AgNPs could be potentially used in biomedical aspects as an anticancer agent in alleviating the problem of acquired drug resistance in chemotherapy.