Inhibition of autophagy enhances the anticancer activity of silver nanoparticles

Abstract

Abbreviations: ANXA5, annexin A5; CASP3, caspase 3, apoptosis-related cysteine peptidase; CTSB, cathepsin B; DLS, dynamic light scattering; DMEM, Dulbecco's Modified Eagle's medium; EGFP-LC3, enhanced green fluorescent protein-tagged LC3; ICP-MS, inductively coupled plasma-mass spectrometry; I-MEF, immortalized mouse embryonic fibroblast; MDC, monodansylcadaverine; MTOR, mechanistic target of rapamycin; P-MEF, primary mouse embryonic fibroblast; PI, propidium iodide; PI3K, phosphoinositide 3-kinase; PtdIns3K, phosphatidylinositol 3-kinase; PVP, polyvinylpyrrolidone; RPS6KB, ribosomal protein S6 kinase, 70 kDa; s.c., subcutaneously; SQSTM1, sequestosome 1; TEM, transmission electron microscopy; TUNEL, terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTPdigoxigenin nick end labeling; UV-Vis, ultraviolet visible; XRD, X-ray diffraction.Silver nanoparticles (Ag NPs) are cytotoxic to cancer cells and possess excellent potential as an antitumor agent. A variety of nanoparticles have been shown to induce autophagy, a critical cellular degradation process, and the elevated autophagy in most of these situations promotes cell death. Whether Ag NPs can induce autophagy and how it might affect the anticancer activity of Ag NPs has not been reported. Here we show that Ag NPs induced autophagy in cancer cells by activating the PtdIns3K signaling pathway. The autophagy induced by Ag NPs was characterized by enhanced autophagosome formation, normal cargo degradation, and no disruption of lysosomal function. Consistent with these properties, the autophagy induced by Ag NPs promoted cell survival, as inhibition of autophagy by either chemical inhibitors or ATG5 siRNA enhanced Ag NPs-elicited cancer cell killing. We further demonstrated that wortmannin, a widely used inhibitor of autophagy, significantly enhanced the antitumor effect of Ag NPs in the B16 mouse melanoma cell model. Our results revealed a novel biological activity of Ag NPs in inducing cytoprotective autophagy, and inhibition of autophagy may be a useful strategy for improving the efficacy of Ag NPs in anticancer therapy.

Silver nanoparticles outperform gold nanoparticles in radiosensitizing U251 cells in vitro and in an intracranial mouse model of glioma

“…[44][45][46][47] In the current study, we found that AuNPs and AgNPs could act as inducers of autophagy, which are in line with earlier reports. 48,49 The mechanism of AuNPs leading to autophagosome accumulation is due to the blockade of autophagy flux, while that of AgNPs the induction of autophagy. 49,50 Moreover, we further demonstrated that their combination with radiation induced greater levels of autophagy in glioma cells.…”

“…48,49 The mechanism of AuNPs leading to autophagosome accumulation is due to the blockade of autophagy flux, while that of AgNPs the induction of autophagy. 49,50 Moreover, we further demonstrated that their combination with radiation induced greater levels of autophagy in glioma cells. Although autophagy is originally defined as type II programmed cell death, researchers have disclosed that autophagy also plays a dual role in cancer development, progression, and treatment.…”

Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species

“…13 In addition, a preferential cytotoxic effect of AgNPs was observed in cells of a breast cancer subtype compared to non-tumorigenic cells derived from the breast, liver, kidney, and monocyte lineages, although the underlying mechanisms were not been determined. 12 Metabolic reprogramming of tumor cells has emerged as a new therapeutic strategy.…”

The Role of Cell Autophagy in Toxicity Caused by Dental Nanomaterials

“…On the other hand, Lin J and his team also had done some researches for silver nanoparticles [70]. They use HeLa EGFP LC3 to detect autophagy.…”

“…The reaction in 7-10 days increased modestly, and the inflammatory response reaches the top on 30 th day. At the same time, according to the TEM, they found that LC3 II's aggregation and LC3 II protein expression obtained under certain silver nanoparticles concentration, early autophagy is induced, and showed a time dependent, decreased gradually, and ATP may play a significant role on induction of liver toxicity after administered silver nanoparticles.On the other hand, Lin J and his team also had done some researches for silver nanoparticles [70]. They use HeLa EGFP LC3 to detect autophagy.…”