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International Journal of Otolaryngology
Volume 2010 (2010), Article ID 523976, 29 pages
http://dx.doi.org/10.1155/2010/523976
Research Article

Ototoxicity from Combined Cisplatin and Radiation Treatment: An In Vitro Study

1Department of Otolaryngology, Singapore General Hospital, Singapore 169608
2Department of Clinical Research, Singapore General Hospital, Singapore 169608

Received 10 June 2010; Revised 29 July 2010; Accepted 10 August 2010

Academic Editor: Leonard P. Rybak

Copyright © 2010 Wong-Kein Low et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective. Combined cisplatin (CDDP) and radiotherapy is increasingly being used to treat advanced head and neck cancers. As both CDDP and radiation can cause hearing loss, it is important to have a better understanding of the cellular and molecular ototoxic mechanisms involved in combined therapy. Procedure. The effects of CDDP, radiation, and combined CDDP-radiation on the OC-k3 cochlear cell line were studied using MTS assay, flow cytometry, Western blotting, and microarray analysis. Results. Compared to using CDDP or radiation alone, its combined use resulted in enhanced apoptotic cell death and apoptotic-related gene expression, including that of FAS. Phosphorylation of p53 at Ser15 (a marker for p53 pathway activation in response to DNA damage) was observed after treatment with either CDDP or radiation. However, posttreatment activation of p53 occurred earlier in radiation than in CDDP which corresponded to the timings of MDM2 and TP53INP1 expression. Conclusion. Enhanced apoptotic-related gene expressions leading to increased apoptotic cell deaths could explain the synergistic ototoxicity seen clinically in combined CDDP-radiation therapy. CDDP and radiation led to differential temporal activation of p53 which suggests that their activation is the result of different upstream processes. These have implications in future antiapoptotic treatments for ototoxicity.