Activation of autophagy by elevated reactive oxygen species rather than released silver ions promotes cytotoxicity of polyvinylpyrrolidone-coated silver nanoparticles in hematopoietic cells

Silver nanoparticles (AgNPs) are the most commonly used engineered nanomaterials in commercialized products because of their antimicrobial activity. Previously, we have shown that polyvinylpyrrolidone (PVP)-coated AgNPs have an anti-leukemia effect against human myeloid leukemia cells; however, whether AgNPs are able to trigger autophagy in normal hematopoietic cells and the role of autophagy in AgNP-induced cytotoxicity remain unclear. In the current study, we observed that AgNPs were taken up by murine pro-B cells (Ba/F3), and then promoted accumulation of autophagosomes, which resulted from the induction of autophagy rather than the blockade of autophagic flux. AgNPs induced cytotoxicity in a dose-dependent manner accompanied by apoptosis and DNA damage through the production of reactive oxygen species (ROS) and the release of silver ions. The ROS-mediated mTOR signaling pathway was responsible for the induction of autophagy. More importantly, the inhibition of autophagy with the addition of 3-methyladenine (3-MA) or silencing of Atg5 significantly attenuated the cytotoxicity of AgNPs in Ba/F3. These findings suggest that autophagy is involved in the cytotoxicity of PVP-coated AgNPs in normal hematopoietic cells, and the inhibition of autophagy is a novel and potent strategy to protect normal hematopoietic cells upon treatment with AgNPs.