Skip to main content Accessibility help

Mechanisms of cisplatin ototoxicity: theoretical review

  • M S Gonçalves (a1), A F Silveira (a2), A R Teixeira (a3) and M A Hyppolito (a4)



Cisplatin is an effective chemotherapeutic agent commonly used in the treatment of malignant tumours, but ototoxicity is a significant side effect.


To discuss the mechanisms of cisplatin ototoxicity and subsequent cell death, and to present the results of experimental studies.

Material and methods:

We conducted a systematic search for data published in national and international journals and books, using the Medline, SciELO, Bireme, LILACS and PubMed databases.


The nicotinamide adenine dinucleotide phosphate oxidase 3 isoform (also termed NOX3) seems to be the main source of reactive oxygen species in the cochlea. These reactive oxygen species react with other molecules and trigger processes such as lipid peroxidation of the plasma membrane and increases in expression of the transient vanilloid receptor potential 1 ion channel.


Cisplatin ototoxicity proceeds via the formation of reactive oxygen species in cochlear tissue, with apoptotic cell death as a consequence.


Corresponding author

Address for correspondence: Dr Maiara S Gonçalves, Avenida Evaldo Behr, 02 Parque Residencial Novo Horizonte, Bairro Camobi, Santa Maria, RS 97110-801, Brazil Fax: +55 55 3301 1166 E-mail:


Hide All
1Wang, D, Lippard, SJ. Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 2005;4:307–20
2Jordan, JA, Schwade, ND, Truelson, JM. Fosfomycin does not inhibit the tumoricidal efficacy of cisplatinum. Laryngoscope 1999;109:1259–62
3Hyppolito, MA, Oliveira, JA. Ototoxicity, otoprotection and self defense of the cochlear outer hair cells [in Brazilian Portuguese]. Medicina (Ribeirão Preto) 2005;38:279–89
4Saleh, S, El-Demerdash, E. Protective effects of L-arginine against cisplatin-induced renal oxidative stress and toxicity: role of nitric oxide. Basic Clin Pharmacol Toxicol 2005;97:91–7
5Bates, DE, Beaumont, SJ, Baylis, BW. Ototoxicity induced by gentamicin and furosemide. Ann Pharmacother 2002;36:446–51
6Ilha, L, Kasse, C, Mesquita Neto, O, Almeida, CR, Cruz, OLM. Cisplatin-induced ototoxicity in guinea pigs: dose-related effects – a functional evaluation [in Brazilian Portuguese]. ACTA ORL/Técnicas em Otorrinolaringologia 2007;25:112–18
7Rybak, LP, Mukherjea, D, Jajoo, S, Ramkumar, V. Cisplatin ototoxicity and protection: clinical and experimental studies. Tohoku J Exp Med 2009;219:177–86
8Rybak, LP, Kelly, T. Ototoxicity: bioprotective mechanisms. Curr Opin Otolaryngol Head Neck Surg 2003;11:328–33
9Schweitzer, VG. Cisplatin-induced ototoxicity: the effect of pigmentation and inhibitory agents. Laryngoscope 1993;103:152
10Hinojosa, R, Riggs, LC, Strauss, M, Matz, GJ. Temporal bone histopathology of cisplatin ototoxicity. Am J Otol 1995;16:731–41
11Lee, JE, Nakagawa, T, Kita, T, Kim, TS, Iguchi, F, Endo, T et al. Mechanisms of apoptosis induced by cisplatin in marginal cells in mouse stria vascularis. ORL J Otorhinolaryngol Relat Spec 2004;66:111–18
12Comis, SD, Rhys-Evans, PH, Osborne, MP, Pickles, JO, Jeffries, DJR, Pearse, HAC. Early morphological and chemical changes induced by cisplatin in the guinea pig organ of Corti. J Laryngol Otol 1986;100:1375–83
13Estrem, SA, Babin, RW, Ryu, JH, Moore, KC. Cis-Diamminedichloroplatinum (II) ototoxicity in the guinea pig. Otolaryngol Head Neck Surg 1981;89:638–45
14Feghali, JG, Lefebvre, PP, Staecker, H, Kopke, R, Frenz, DA, Malgrange, B et al. Mammalian auditory hair cell regeneration/repair and protection: a review and future directions. Ear Nose Throat J 1998;77:276–85
15Simon, T, Hero, B, Dupuis, W, Selle, B, Berthold, F. The incidence of hearing impairment after successful treatment of neuroblastoma. Klin Pediatr 2002;214:149–52
16Casares, C, Ramírez-Camacho, R, Trinidad, A, Roldán, A, Jorge, E, García-Berrocal, JR. Reactive oxygen species in apoptosis induced by cisplatin: review of physiopathological mechanisms in animal models. Eur Arch Otorhinolaryngol 2012;269:2455–9
17Stavroulaki, P, Apostolopoulos, N, Segas, J, Tsakanikos, M, Adamopoulos, G. Evoked otoacoustic emissions – an approach for monitoring cisplatin induced ototoxicity in children. Int J Pediatr Otorhinolaryngol 2001;59:4757
18Garcia, AP, Iório, MCM, Petrilli, AS. Audiological monitoring of cisplatin exposed patients [in Brazilian Portuguese]. Rev Bras Otorrinolaringol 2003;69:215–21
19Li, Y, Womer, RB, Silber, JH. Predicting cisplatin ototoxicity in children: influence of age and the cumulative dose. Eur J Cancer 2004;40:2445–51
20Schneider, CD, Oliveira, AR. Oxygen free radicals and exercise: mechanisms of synthesis and adaptation to physical training [in Brazilian Portuguese]. Rev Bras Med Esporte 2004;10:308–13
21Ferreira, ALA, Matsubara, LS. Free radicals: concepts, diseases, defense system and oxidative stress [in Brazilian Portuguese]. Rev Assoc Med Bras 1997;43:61–8
22Barreiros, ALBS, David, JM, David, JP. Oxidative stress: relations between the formation of reactive species and the organism's defense [in Brazilian Portuguese]. Quim Nova 2006;29:113–23
23Freeman, BA, Crapo, JD. Biology of disease: free radical and tissue injury. Lab Invest 1982;47:412–26
24Kumar, V, Abbas, AK, Fausto, N. Cellular injury, cell adaptation and cell death. In: Robbins and Cotran: Pathologic Basis of Disease, 7th edn.Philadelphia: Elsevier, 2005;1148
25Ross, D, Moldeus, P. Antioxidant defense systems and oxidative stress. In: Vigo-Pelfrey, C. Membrane Lipid Oxidation. Boca Raton: CRC Press, 1991;151–70
26Gutteridge, JMC, Halliwell, B. Antioxidants: molecules, medicines and myths. Biochem Biophys Res Commun 2010;393:561–4
27Rybak, LP, Husain, K, Morris, C, Whitworth, C, Somani, S. Effect of protective agents against cisplatin ototoxicity. Am J Otol 2000;21:513–20
28Campbell, KCM, Kalkanis, J, Glatz, FR. Ototoxicity: mechanisms, protective agents and monitoring. Curr Opin Otol Head Neck Sur 2000;8:436–40
29Van Rujven, MWM, De Groot, JCMJ, Hendriksen, F, Smoorenburg, GF. Immunohistochemical detection of platinated DNA in the cochlea of cisplatin-treated guinea pigs. Hear Res 2005;203:112–21
30Mukherjea, D, Jajoo, S, Whitworth, CA, Bunch, JR, Turner, JG, Rybak, LP et al. Short interfering RNA against transient receptor potential vanilloid-1 attenuates cisplatin-induced hearing loss in the rat. J Neurosci 2008;28:13056–65
31Bánfi, B, Malgrange, B, Knisz, J, Steger, K, Dubois-Dauphin, M, Krause, K-H. NOX3, a superoxide-generating NADPH oxidase of the inner ear. J Biol Chem 2004;279:46065–72
32Rybak, LP. Mechanisms of cisplatin ototoxicity and progress in otoprotection. Curr Opin Otolaryngol Head Neck Surg 2007;15:364–9
33Ikeda, K, Sunose, H, Takasaka, T. Effects of free radicals on the intracellular calcium concentration in the isolated hair cell of the guinea pig cochlea. Acta Otolaryngol 1993;113:137–41
34Pigeolet, E, Corbisier, P, Houbion, A, Lambert, D, Michiels, C, Raes, M et al. Glutathione peroxidase, superoxide dismutase and catalase inactivation by peroxides and oxygen derived free radicals. Mech Ageing Dev 1990;50:283–97
35Caterina, MJ, Schumacher, MA, Tominaga, M, Rosen, TA, Levine, JD, Julius, D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389:816–24
36Southall, MD, Li, T, Gharibova, LS, Pei, Y, Nicol, GD, Travers, JB. Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes. J Pharmacol Exp Ther 2003;304:217–22
37Zheng, J, Dai, C, Steyger, PS, Kim, Y, Vass, Z, Ren, T et al. Vanilloid receptors in hearing: altered cochlear sensitivity by vanilloids and expression of TRPV1 in the organ of corti. J Neurophysiol 2003;90:444–55
38Devarajan, P, Savoca, M, Castaneda, MP, Park, MS, Esteban-Cruciani, N, Kalinec, G et al. Cisplatin-induced apoptosis in auditory cells: role of death receptor and mitochondrial pathways. Hear Res 2002;174:4554
39Ravi, R, Somani, SM, Rybak, LP. Mechanism of cisplatin ototoxicity: antioxidant system. Pharmacol Toxicol 1995;76:386–94
40Strayer, DS, Rubin, E. Cell injury. In: Rubin, E, Gorstein, F, Rubin, R, Schwarting, R, Strayer, D. Rubin's Pathology: Clinicopathologic Foundations of Medicine, 4th edn [in Brazilian Portuguese]. São Paulo: Guanabara-Koogan, 2006;239
41Hengartner, MO. The biochemistry of apoptosis. Nature 2000;407:770–6
42Huang, T, Cheng, AG, Stupak, H, Liu, W, Kim, A, Staecker, H et al. Oxidative stress-induced apoptosis of cochlear sensory cells: otoprotective strategies. Int J Dev Neurosci 2000;18:259–70
43Adams, JM, Cory, S. The Bcl-2 protein family: arbiters of cell death. Science 1998;281:1322–6
44Strasser, A, O'Connor, L, Dixit, VM. Apoptosis signaling. Annu Rev Biochem 2000;69:217–45
45Boatright, KM, Salvesen, GS. Mechanisms of caspase activation. Curr Opin Cell Biol 2003;15:725–31
46Sharifia, AM, Eslami, H, Larijani, B, Davoodi, J. Involvement of caspase-8, 9, and 3 in high glucose-induced apoptosis in PC12 cells. Neurosci Lett 2009;459:4751
47Grivicich, I, Regner, A, Rocha, AB. Apoptosis: programmed cell death [in Brazilian Portuguese]. Rev Bras Cancerol 2007;53:335–43
48Harris, MH, Thompson, CB. The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ 2000;7:1182–91
49Borner, C. The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol 2003;39:615–47
50Golstein, JC, Waterhouse, NJ, Juin, P, Evan, GI, Green, DR. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nature Cell Biol 2000;2:156–62
51Thornberry, NA, Lazebnik, Y. Caspases: enemies within. Science 1998;281:1312–16
52Amarante-Mendes, GP, Green, DR. The regulation of apoptotic cell death. Braz J Med Biol Res 1999;32:1053–61
53Paronlin, MB, Reason, IJ. Apoptosis as a mechanism of tissue injury in hepatobiliary diseases [in Brazilian Portuguese]. Arq Gastroenterol São Paulo 2001;38:3844
54Alam, SA, Ikeda, K, Oshima, T, Suzuki, M, Kawase, T, Kikuchi, T et al. Cisplatin-induced apoptotic cell death in Mongolian gerbil cochlea. Hear Res 2000;141:2838
55Liu, W, Staecker, H, Stupak, H, Malgrange, B, Lefebvre, P, Van De Water, TR. Caspase inhibitors prevent cisplatin-induced apoptosis of auditory sensory cells. Neuroreport 1998;9:2609–14
56Cheng, PW, Liu, SH, Hsu, CJ, Lin-Shiau, SY. Correlation of increased activities of Na + , K + -ATP-ase and Ca2 + -ATPase with the reversal of cisplatin ototoxicity induced by D-methionine in guinea pigs. Hear Res 2005;205:102–9
57Cardinaal, RM, de Groot, JC, Huizing, EH, Veldman, JE, Smoorenburg, GF. Histological effects of co-administration of an ACTH(4-9) analog ORG 2766 on cisplatin ototoxicity in the albino guinea pig. Hear Res 2000;144:157–67
58Kasse, CA, Hyppolito, MA, Cruz, OLM, Oliveira, JAA. Ototoxicity and otoprotection [in Brazilian Portuguese]. Rev Bras Med Otorrinolaringol 2008;4:105–15
59Rybak, L, Whitworth, C, Somani, S. Application of antioxidants and other agents to prevent cisplatin ototoxicity. Laryngoscope 1999;109:1740–4
60Freitas, MR, Figueiredo, AA, Brito, GAC, Leitão, RFC, Carvalho, JV Jr, Gomes, RM Jr et al. The role of apoptosis in cisplatin-induced ototoxicity in rats [in Brazilian Portuguese]. Braz J Otorhinolaryngol 2009;75:745–52
61Sha, SH, Taylor, R, Forge, A, Schacht, J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear Res 2001;155:18
62Usami, S, Hjelle, OP, Ottersen, OP. Differential cellular distribution of glutathione – an endogenous antioxidant – in the guinea pig inner ear. Brain Res 1996;743:337–40
63Muldoon, LL, Pagel, MA, Kroll, RA, Brummett, RE, Doolittle, ND, Zuhowski, EG et al. Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity. Clin Cancer Res 2000;6:309–15
64Hyppolito, MA, Oliveira, JAA, Lessa, RM, Rossato, M. Amifostine otoprotection to cisplatin ototoxicity: a guinea pig study using otoacoustic emission distortion products (DPOEA) and scanning electron microscopy [in Brazilian Portuguese]. Rev Bras Otorrinolaringol 2005;71:168273
65Hyppolito, MA, Oliveira, JAA, Rossato, M, Holanda, F. Cisplatin ototoxicity and otoprotector to ciliated cells by ginkgo biloba extract: anatomic and electrophysiologic study [in Brazilian Portuguese]. Rev Bras Otorrinolaringol 2003;69:504–11
66Kalkanis, JG, Whitworth, C, Rybak, LP. Vitamin E reduces cisplatin ototoxicity. Laryngoscope 2004;114:538–42
67Feghali, JG, Liu, W, Van De Water, TR. L-N-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity. Laryngoscope 2001;111:1147–55
68Fetoni, AR, Ralli, M, Sergi, B, Parrilla, C, Troiani, D, Paludetti, G. Protective effects of N-acetylcysteine on noise-induced hearing loss in guinea pigs. Acta Otorhinolaryngol Ital 2009;29:70–5
69Riga, MG, Chelis, L, Kakolyris, S, Papadopoulos, S, Stathakidou, S, Chamalidou, E et al. Transtympanic injections of N-acetylcysteine for the prevention of cisplatin-induced ototoxicity: a feasible method with promising efficacy. Am J Clin Oncol 2013;36:16


Mechanisms of cisplatin ototoxicity: theoretical review

  • M S Gonçalves (a1), A F Silveira (a2), A R Teixeira (a3) and M A Hyppolito (a4)


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed