title: Activation of apoptotic pathways in the absence of cell death in an inner-ear immortomouse cell line.
abstract: Aminoglycoside antibiotics and cisplatin (CDDP) are the major ototoxins of clinical medicine due to their capacity to cause significant and permanent hearing loss by targeting the mammalian sensory cells. Understanding the pathogenesis of damage is the first step in designing effective prevention of drug-induced hearing loss. In-vitro systems greatly enhance the efficiency of biochemical and molecular investigations through ease of access and manipulation. HEI-OC1, an inner ear cell line derived from the immortomouse, expresses markers for auditory sensory cells and, therefore, is a potential tool to study the ototoxic mechanisms of drugs like aminoglycoside antibiotics and CDDP. HEI-OC1 cells (and also HeLa cells) efficiently take up fluorescently tagged gentamicin and respond to drug treatment with changes in cell death and survival signaling pathways. Within hours, the c-Jun N-terminal kinase pathway and the transcription factor AP-1 were activated and at later times, the "executioner caspase", caspase-3. These responses were robust and elicited by both gentamicin and kanamycin. However, despite the initiation of apoptotic pathways and transient changes in nuclear morphology, cell death was not observed following aminoglycoside treatment, while administration of CDDP led to significant cell death as determined by flow cytometric measurements; β-galactosidase analysis ruled out senescence in gentamicin-treated cells. The ability to withstand treatment with aminoglycosides but not with CDDP suggests that this cell line might be helpful in providing some insight into the differential actions of the two ototoxic drugs.
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, Medical University of South Carolina, 39 Sabin Street, Charleston, SC 29425, USA.
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Chen
authors.forename: Kayla
authors.initials: K
authors.lastname: Hill
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Guan
authors.forename: Jochen
authors.initials: J
authors.lastname: Schacht
authors.forename: Su-Hua
authors.initials: SH
authors.lastname: Sha
mesh_terms: D000617:Aminoglycosides / Q000633:toxicity; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002945:Cisplatin / Q000633:toxicity; D007758:Ear, Inner / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005839:Gentamicins / Q000493:pharmacokinetics / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D005839:Gentamicins; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002945:Cisplatin