title: Fluazinam-induced apoptosis of SH-SY5Y cells is mediated by p53 and Bcl-2 family proteins.
abstract: A number of epidemiological studies have demonstrated a strong association between the incidence of neurodegenerative disease and pesticide exposure. Fluazinam (FZN) is a preventative fungicide from the pyridinamine group that was introduced in the 1990 s and that quickly established itself as a new standard for the control of blight caused by Phytophthora infestans in potatoes. We used human neuroblastoma SH-SY5Y cells to investigate mechanisms of neuronal cell death in response to FZN and showed that FZN was cytotoxic to SH-SY5Y cells in a concentration- and time-dependent manner. Additionally, we showed that FZN treatment significantly decreased the neuron numbers including dopaminergic neurons and mitochondrial complex I activity. The cytotoxic effects of FZN were associated with an increase in reactive oxygen species (ROS) generation because pretreatment with N-acetyl cysteine, an anti-oxidant, reduced cell death. We showed that neuronal cell death in response to FZN was due to apoptosis because FZN increased cytochrome C release into the cytosol and activated caspase-3 through the accumulation of p53. FZN also reduced the levels of Bcl-2 protein but increased the levels of Bax. Our results provide insight into the molecular mechanisms of FZN-induced apoptosis in neuronal cells.
authors: Department of Pharmacology, College of Medicine, Hanyang University, Republic of Korea.
authors: Jeong Eun
authors: JE
authors: Lee
authors: Jin Sun
authors: JS
authors: Kang
authors: In Chul
authors: IC
authors: Shin
authors: Soo-Jin
authors: SJ
authors: Lee
authors: Dong-Hoon
authors: DH
authors: Hyun
authors: Kyung Suk
authors: KS
authors: Lee
authors: Hyun Chul
authors: HC
authors: Koh
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000631:Aminopyridines / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010575:Pesticides / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D000975:Antioxidants; C494826:BAX protein, human; D010575:Pesticides; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C075780:fluazinam; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D042967:Electron Transport Complex I; D000111:Acetylcysteine