Nanosilver inhibits the progression of pancreatic cancer by inducing a paraptosis-like mixed type of cell death

Silver has been in clinical use since ancient times and silver nanoparticles (AgNPs) have attracted attention in cancer therapy. We investigated the mechanisms by which AgNPs inhibit pancreatic ductal adenocarcinoma (PDAC). AgNPs were synthesized and 3 human PDAC and 2 nonmalignant primary cell lines were treated with AgNPs. MTT, MAPK, colony, spheroid and scratch assays, Western blotting, TEM, annexin V, 7-AAD, and H2DCFDA staining, FACS analysis, mRNA array and bioinformatics analyses, tumor xenograft transplantation, and immunohistochemistry of the treated cells were performed. We found that minimal AgNPs amounts selec-tively eradicated PDAC cells within a few hours. AgNPs inhibited cell migration and spheroid and colony for-mation, damaged mitochondria, and induced paraptosis-like cell death with the presence of cytoplasmic vacuoles, dilation of the ER and mitochondria, ROS formation, MAPK activity, and p62 and LC3b expression, whereas effects on the nucleus, DNA fragmentation, or caspases were not detectable. AgNPs strongly decreased tumor xenograft growth without side effects and reduced the expression of markers for proliferation and DNA repair, but upregulated paraptosis markers. The results highlight nanosilver as complementary agent to improve the therapeutic efficacy in pancreatic cancer.

Automated summary

This study investigated the mechanisms by which silver nanoparticles inhibit pancreatic ductal adenocarcinoma (PDAC). The results showed that minimal amounts of silver nanoparticles selectively eradicated PDAC cells and inhibited cell migration, spheroid and colony formation. Furthermore, silver nanoparticles damaged mitochondria and induced paraptosis-like cell death. In addition, silver nanoparticles decreased tumor xenograft growth without side effects and reduced the expression of markers for proliferation and DNA repair, but upregulated paraptosis markers. This highlights the potential of silver nanoparticles as a complementary agent to improve the therapeutic efficacy in pancreatic cancer.