Exploring the Potentials of Silver Nanoparticles in Overcoming Cisplatin Resistance in Lung Adenocarcinoma: Insights from Proteomic and Xenograft Mice 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 toward multidrug-resistant cancer cells. Herein, we employed quantitative proteomics to investigate the cytotoxic mechanisms of AgNPs and their potential anticancer properties on both cisplatin-sensitive (A549 cells) and -resistant (A549/DDP cells) human lung adenocarcinoma using quantitative proteomics and mice xenograft model approaches. We first performed cytotoxicity tests and found that AgNPs exerted 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 the VEGF signaling pathway, repressing p53-mediated pathways, promoting cell cycle arrest, etc. Additionally, we found that AgNPs induced ROS generation and disrupted mitochondrial function and respiration in the A549 and A549/DDP cells. Lastly, animal studies using established mice xenograft models administered with AgNPs showed that AgNPs exhibit similar antitumoral effects on both A549 and A549/DDP-bearing mice. Overall, our investigations showed that AgNPs could effectively induce cell death in lung adenocarcinoma regardless of their sensitivities to cisplatin, suggesting that AgNPs could be potentially used in biomedical aspects as anticancer agents in alleviating the problem of acquired drug resistance in chemotherapy.