Mechanisms of Apoptosis Induced by Cisplatin in Marginal Cells in Mouse Stria Vascularis

Abstract

Degeneration of the stria vascularis (SV) is amongst the major causes of cisplatin (CDDP)-induced hearing impairment. The pathways of apoptosis occurring in the SV due to CDDP were examined using a mouse experimental model. Temporal bones of adult C57BL/6 mice were collected on days 3, 7 and 14 after the local application of CDDP. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and immunostaining for apoptosis-related proteins or reactive radical species were employed for analysis. Local application of CDDP caused apoptotic cell death of marginal cells 3 days after CDDP treatment. Immunohistochemical analyses demonstrated activation of caspase-3 and -9, but not -8, and redistribution of cytochrome c in affected marginal cells, indicating a caspase-dependent, mitochondrion-mediated apoptotic pathway in marginal cells. Temporary expression of hydroxynonenal, nitrotyrosine and inducible nitric oxide synthase in the SV was observed at the induction of apoptosis in marginal cells. CDDP toxicity generates reactive radical species in the SV, which causes mitochondrial membrane permeabilization leading to apoptosis of marginal cells.

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

“…These authors have suggested that marginal cells of the stria vascularis have a major role in the early events of cisplatin ototoxicity. The more extensive effects observed in our study could be due to the different times used to analyse the effects of the drug: 7 days (present study) vs 1-3 days (Lee et al, 2004;Thomas et al, 2006), following cisplatin administration. The results from of our study indicate that a profound re-examination of the possible role of the apoptosis of different inner ear cells following cisplatin treatment should be undertaken.…”

“…The impairment of K þ -recycling process that is essential to the endocochlear potential, is a toxic effect of cisplatin induced by apoptosis of type I spiral ligament fibrocytes (Liang et al, 2005) and by the direct apoptotic effect of cisplatin on the stria vascularis, responsible for the decreased cellular Na þ , K þ ATPase and Ca 2 þ ATPase activities (Cheng et al, 2005). Apoptosis in the stria vascularis cells on day 3 following CDDP treatment has been suggested by Lee et al (2004). Morphologically, oedema formation in the stria vascularis was followed by severe atrophy after CDDP treatment.…”

“…This antineoplastic effect is mediated by the platination of nucleophilic centres in DNA bases, leading to intra-or inter-strand crosslinking of the bases, to abnormal base pairing or to DNA strand breakage. One important way by which cisplatin-DNA adducts may kill cells is by the induction of programmed cell death or apoptosis (Lee et al, 2004). A high accumulation of platinum-DNA adducts has been observed in the nuclei of marginal cells of the stria vascularis, but not in OHCs that have been discussed as the main target of cisplatin-induced cell damage (Thomas et al, 2006).…”

“…Programmed cell death or apoptosis has been associated with the administration of several anticancer drugs, including CDDP (Lee et al, 2004;Matsuhashi et al, 2005). This active form of cell death is characterized by morphological changes such as cell shrinkage, chromatin condensation and fragmentation of DNA, which often requires the synthesis of new proteins called caspases (cysteine-requiring aspartate proteases).…”

The Protective Effect of Cortexin on Cisplatin-Induced Ototoxicity

“…It is thought that the autotoxic side effect of cisplatin is caused by binding to DNA and causing apoptosis and activation of inflammatory cascade pathway leading to oxidative stress in the cell [6] . Reactive oxygen products produced after oxidative stress increase alfahydrate, malandialdehyde, toxic lipid peroxidase levels by allowing lipid peroxidation of protective antioxidant molecules against cochlear tissues [7] . The target regions that are mainly affected by cell damage mechanisms are the spiral ganglion cells, the lateral wall and the hairy cells in the cortical organ [6] .…”