title: Water-soluble germanium nanoparticles cause necrotic cell death and the damage can be attenuated by blocking the transduction of necrotic signaling pathway.
abstract: Water-soluble germanium nanoparticles (wsGeNPs) with allyamine-conjugated surfaces were fabricated and emit blue fluorescence under ultraviolet light. The wsGeNP was physically and chemically stable at various experimental conditions. Cytotoxicity of the fabricated wsGeNP was examined. MTT assay demonstrated that wsGeNP possessed high toxicity to cells and clonogenic survival assay further indicated that this effect was not resulted from retarding cell growth. Flow cytometric analysis indicated that wsGeNP did not alter the cell cycle profile but the sub-G1 fraction was absent from treated cells. Results from DNA fragmentation and propidium iodide exclusion assays also suggested that apoptotic cell death did not occur in cells treated with wsGeNP. Addition of a necrosis inhibitor, necrostatin-1, attenuated cell damage and indicated that wsGeNP caused necrotic cell death. Cell signaling leads to necrotic death was investigated. Intracellular calcium and reactive oxygen species (ROS) levels were increased upon wsGeNP treatment. These effects can be abrogated by BAPTA-AM and N-acetyl cysteine respectively, resulting in a reduction in cell damage. In addition, wsGeNP caused a decrease in mitochondrial membrane potential (MMP) which could be recovered by cyclosporine A. The cellular signaling events revealed that wsGeNP increase the cellular calcium level which enhances the production of ROS and leads to a reduction of MMP, consequentially results in necrotic cell death.
authors: Institute of Molecular and Cellular Biology, and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors: Yu-Hsin
authors: YH
authors: Ma
authors: Chin-Ping
authors: CP
authors: Huang
authors: Jia-Shiuan
authors: JS
authors: Tsai
authors: Mo-Yuan
authors: MY
authors: Shen
authors: Yaw-Kuen
authors: YK
authors: Li
authors: Lih-Yuan
authors: LY
authors: Lin
mesh_terms: D000818:Animals; D016466:CHO Cells / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000032:analysis; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D006224:Cricetinae; D005857:Germanium / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053768:Metal Nanoparticles / Q000633:toxicity*; D009336:Necrosis / Q000139:chemically induced* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D017550:Spectroscopy, Fourier Transform Infrared; D013778:Tetrazolium Salts; D013844:Thiazoles; D018675:Toxicity Tests
chemical_list: D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D005857:Germanium; D053148:Caspase 3; C022616:thiazolyl blue; D002118:Calcium