title: Activation of autophagy by elevated reactive oxygen species rather than released silver ions promotes cytotoxicity of polyvinylpyrrolidone-coated silver nanoparticles in hematopoietic cells.
abstract: 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.
authors.affiliation: State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, PR China. guning@seu.edu.cn.
authors.forename: Lingying
authors.initials: L
authors.lastname: Zhu
authors.forename: Dawei
authors.initials: D
authors.lastname: Guo
authors.forename: Lili
authors.initials: L
authors.lastname: Sun
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Huang
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Ma
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Lun
authors.initials: L
authors.lastname: Xiao
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ning
authors.initials: N
authors.lastname: Gu
mesh_terms: D000818:Animals; D000071182:Autophagosomes; D001343:Autophagy; D002460:Cell Line; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007477:Ions; D053768:Metal Nanoparticles; D051379:Mice; D011205:Povidone / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D012834:Silver / Q000737:chemistry*
chemical_list: D007477:Ions; D017382:Reactive Oxygen Species; D012834:Silver; D011205:Povidone