title: Apoptosis induced neurotoxicity of Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) via mitochondria-mediated pathway in PC12 cells.
abstract: The severe toxicity of antitumor organotin (IV) compounds limits their application in clinic, however, the toxic mechanism is still unclear. Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) (DBDCT), an antitumor agent with high activity and obvious neurotoxicity was chosen as a typical diorganotin (IV) compound to investigate its neurotoxic mechanism using PC12 cells and comprehensive methods. Treatment with DBDCT resulted in a dose- and time-dependent growth inhibition of PC12 cells. The changes in cell morphology were observed using light microscopy, fluorescence microscopy and transmission electron microscopy. PC12 cell apoptosis induced by DBDCT was confirmed by annexin V/propidium iodide staining, and characterized by cleavage of caspase-9 and caspase-3 proteins. DBDCT induced the release of cytochrome c from the mitochondria to the cytosol and the generation of reactive oxygen species. DBDCT up-regulated the expression of Bax, down-regulated the expression of Bcl-2, and significantly increased the ratio of Bax/Bcl-2. DBDCT also caused the phosphorylation of JNK and p38(MAPK). In rats exposed to DBDCT, apoptosis was also observed in brain, as shown by the detection of cleaved caspase-9 and caspase-3 proteins and increased TUNEL positive staining. In conclusion, the results demonstrated that DBDCT caused the neurotoxicity by inducing apoptosis via mitochondria-mediated pathway.
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ge
authors.forename: Wen-Hua
authors.initials: WH
authors.lastname: Ma
authors.forename: Yun-Lan
authors.initials: YL
authors.lastname: Li
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009947:Organotin Compounds / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D009947:Organotin Compounds; C542282:dibutyldi(4-chlorobenzohydroxamato)tin(IV); D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases