Cisplatin ototoxicity and protection: clinical and experimental studies

Abstract

Cisplatin is a chemotherapeutic agent that is widely used to treat a variety of malignant tumors. Serious dose-limiting side effects like ototoxicity, nephrotoxicity and neurotoxicity occur with the use of this agent. This review summarizes recent important clinical and experimental investigations of cisplatin ototoxicity. It also discusses the utility of protective agents employed in patients and in experimental animals. The future strategies for limiting cisplatin ototoxicity will need to avoid interference with the therapeutic effect of cisplatin in order to enhance the quality of life of patients receiving this important anti-tumor agent.

Fig. 1. An overview of cisplatin induced pathways in cochlear ototoxicity in the different areas of the cochleae and the potential inhibitors

Cisplatin administration causes induction/activation of TRPV1 and NOX3, both of which lead to increased ROS generation. One common pathway by which increased ROS produced apoptosis in all the regions of the cochleae is by production of free superoxide radical which reacts with water to form hydrogen peroxide that will react with iron to form highly reactive hydroxyl radical. This in turn interacts with poly unsaturated fatty acids (PUFA) of the cell membrane to form 4-hydroxynonenal (4-HNE), which is a highly toxic aldehyde which leads to cell death. In addition to this pathway cisplatin has also been shown to activate NFκB which induces the formation of nitric oxide (NO) by upregulating the enzyme iNOS in the lateral wall (stria vascularis and spiral ligament, represented as SVA/SL) of the cochlea. This NO release reacts with superoxide to form peroxynitrite which will activate a caspase cascade followed by apoptosis. In the spiral ganglion (SG), cisplatin has been shown to upregulate the expression of high mobility group (HMG1) protein which upregulates iNOS and can cause cell death via either the caspase cascade or via the 4-HNE pathway in this tissue.

Fig. 2. siRNA for TRPV1 protein shows decreased immunoreactivity in the rat cochlea

Scrambled siRNA or TRPV1 siRNA (0.9 µg) were administered to the rat cochlea by round window application, followed by vehicle or cisplatin (13 mg/kg; i.p.) treatment 48 h later. Animals were anesthetized and euthanized 72 h post cisplatin treatment, the cochleae were excised and processed for TRPV1 immunohistochemistry. Midmodiolar sections of the cochlea (magnification, 100×) are shown in the images above. Cisplatin treatment showed increased immunolabeling in the organ of Corti, spiral ganglion and stria vascularis. Administration of TRPV1 siRNA significantly decreased both basal and cisplatin-induced TRPV1 immunoreactivity in all the three regions examined. This difference in fluorescence intensity has been represented as a bar graph in the right panel. The data are presented as the mean ± SEM of 3 animals for each treatment group. Abbreviations: SVA, OC and SG represent stria vascularis, organ of Corti and stria vascularis, respectively. Asterisk (*) indicate statistically significant increase in TRPV1 immunolabeling as compared to vehicle treated controls ( p < 0.05), while (**) indicates statistically significant difference from the cisplatin group ( p < 0.05). (Mukherjea et al. 2008; This image has been republished with permission from Journal of Neuroscience).