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siRNA-mediated knock-down of NOX3: therapy for hearing loss?

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Abstract

Cisplatin is a widely used chemotherapeutic agent that causes significant hearing loss. Previous studies have shown that cisplatin exposure is associated with increase in reactive oxygen species (ROS) in the cochlea. The inner ear expresses a unique isoform of NADPH oxidase, NOX3. This enzyme may be the primary source of ROS generation in the cochlea. The knockdown of NOX3 by pretreatment with siRNA prevented cisplatin ototoxicity, as demonstrated by preservation of hearing thresholds and inner ear sensory cells. Trans-tympanic NOX3 siRNA reduced the expression of NOX3 and biomarkers of cochlear damage, including transient receptor vanilloid 1 (TRPV1) channel and kidney injury molecule-1 (KIM-1) in cochlear tissues. In addition, siRNA against NOX3 reduced apoptosis as demonstrated by TUNEL staining, and prevented the increased expression of Bax and abrogated the decrease in Bcl2 expression following cisplatin administration. Trans-tympanic administration of siRNA directed against NOX3 may provide a useful method of attenuating cisplatin ototoxicity. In this paper, we review recent publications dealing with the role of NOX3 in ototoxicity and the effects of siRNA against cisplatin-induced hearing loss.

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References

  1. McKeage MJ (1995) Comparative adverse effect profiles of platinum drugs. Drug Saf 13:228–244

    Article  PubMed  CAS  Google Scholar 

  2. Li Y, Womer RB, Silber JH (2004) Predicting cisplatin ototoxicity in children: influence of age and the cumulative dose. Eur J Cancer 40:2445–2451

    Article  PubMed  CAS  Google Scholar 

  3. Kushner BH, Budnick A, Kramer K, Modak S, Cheung N-KV (2006) Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer 107:417–422

    Article  PubMed  CAS  Google Scholar 

  4. Kopelman J, Budnick AS, Sessions RB, Kramer MB, Wong GY (1988) Ototoxicity of high dose cisplatin by bolus administration in patients with advanced cancer and normal hearing. Laryngoscope 98:858–864

    Article  PubMed  CAS  Google Scholar 

  5. Bokemeyer C, Berger CC, Hartmann JT, Kollmansberger C, Schmoll HJ, Kuczyk MA, Kanz L (1998) Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer. Br J Cancer 77:1355–1362

    Article  PubMed  CAS  Google Scholar 

  6. Chen WC, Jackson A, Budnick AS, Pfister DG, Kraus DH, Hunt MA, Stambuk H, Levegrun S, Wolden SL (2006) Sensorineural hearing loss in combined modality treatment of nasopharyngeal carcinoma. Cancer 106:820–829

    Article  PubMed  Google Scholar 

  7. Fleischman KW, Stadnicki SW, Ethier MF, Schaeppi U (1975) Ototoxicity of cis-dichlorodiammine platinum (II) in the guinea pig. Toxicol Appl Pharmacol 22:320–332

    Article  Google Scholar 

  8. Kamimura T, Whitworth CA, Rybak LP (1999) Effects of 4-methylthiobenzoic acid on cisplatin ototoxicity in the rat. Hear Res 131:117–127

    Article  PubMed  CAS  Google Scholar 

  9. Sluyter S, Klis SF, de Groot JC, Smoorenburg GF (2003) Alterations in the stria vascularis in relation to cisplatin ototoxicity and recovery. Hear Res 185:49–56

    Article  PubMed  CAS  Google Scholar 

  10. Campbell KC, Meech RP, Rybak LP, Hughes LF (1999) d-methionine protects against cisplatin damage to the stria vascularis. Hear Res 138:13–28

    Article  PubMed  CAS  Google Scholar 

  11. Clerici WJ, DiMartino DL, Prasad MR (1995) Direct effects of reactive oxygen species on cochlear outer hair cell shape in vitro. Hear Res 84:30–40

    Article  PubMed  CAS  Google Scholar 

  12. Clerici WJ, Yang L (1996) Direct effects of intraperilymphatic reactive oxygen species on cochlear function. Hear Res 101:14–22

    Article  PubMed  CAS  Google Scholar 

  13. Kopke RD, Liu W, Gabaizadeh R, Jacono A, Feghali J, Spray D, Garcia P, Steinman H, Malgrange B, Ruben RJ, Rybak L, Van de Water TR (1997) Use of organotypic cultures of Corti’s organ to study the protective effects of antioxidant molecules on cisplatin induced damage of auditory hair cells. Am J Otol 18:559–571

    PubMed  CAS  Google Scholar 

  14. Dehne N, Lautermann J, Petrat F, Rauen U, de Groot H (2001) Cisplatin ototoxicity: involvement of iron and enhanced formation of superoxide anion radicals. Toxicol Appl Pharmacol 174:27–34

    Article  PubMed  CAS  Google Scholar 

  15. Banfi B, Malgrange B, Knisz J, Steger K, Dubois-Dauphin M, Krause K-H (2004) NOX3, a superoxide-generating NADPH oxidase of the inner ear. J Biol Chem 279:46065–46072

    Article  PubMed  CAS  Google Scholar 

  16. Rybak LP, Somani S (1999) Ototoxicity: amelioration by protective agents. Ann NY Acad Sci 884:143–151

    PubMed  CAS  Google Scholar 

  17. Lee JE, Nakagawa T, Kim TS, Endo T, Shiga A, Iguchi F, Lee SH, Ito J (2004) Role of reactive radicals in degeneration of the auditory system of mice following cisplatin treatment. Acta Otolaryngol 124:1131–1135

    Article  PubMed  CAS  Google Scholar 

  18. Lee JE, Nakagawa T, Kita T, Kim TS, Endo T, Shiga A, Iguchi F, Lee SH, Ito J (2004) Mechanisms of apoptosis induced by cisplatin in marginal cells in mouse stria vascularis. ORL J Otorhinolaryngol Relat Spec 66:111–118

    Article  PubMed  CAS  Google Scholar 

  19. Ikeda K, Sunose H, Takasaka T (1993) Effects of free radicals on the intracellular calcium concentration in the isolated hair cell of the guinea pig cochlea. Acta Otolaryngol 113:137–141

    Article  PubMed  CAS  Google Scholar 

  20. Pigeolet E, Corbisier P, Houbion A, Lambert D, Michiels C, Raes M, Zachary MD, Remacle J (1990) Glutathione peroxidase, superoxide dismutase, and catalase inactivation by peroxides and oxygen derived free radicals. Mech Aging Dev 51:283–297

    Article  PubMed  CAS  Google Scholar 

  21. Watanabe K, Inai S, Jinnouchi K, Baba S, Yagi T (2003) Expression of caspase activated deoxyribonuclease (CAD) and caspase 3 (CPP32) in the cochlea of cisplatin (CDDP)-treated guinea pigs. Auris Nasis Larynx 30:219–225

    Article  Google Scholar 

  22. Paffenholz R, Bergstrom RA, Pasutto F, Wabnitz P, Munroe RJ, Jagla W, Heinzmann U, Marquardt lA, Bareiss A, Laufs J, Russ A, Stumm G, Schimenti JC, Bergstrom DE (2004) Vestibular defects in head-tilt mice result from mutations in Nox3, encoding an NADPH oxidase. Genes Dev 18:486–491

    Article  PubMed  CAS  Google Scholar 

  23. Flaherty JF, Fairfield HE, Spruce CA, McCarty CM, Bergstrom DE (2011) Molecular characterization of an allelic series of mutations in the mouse Nox3 gene. Mamm Genome 22:156–169

    Article  PubMed  CAS  Google Scholar 

  24. Darrat I, Ahmad N, Seidman K, Seidman MD (2007) Auditory research involving antioxidants. Curr Opin Otolaryngol Head Neck Surg 15:358–363

    Article  PubMed  Google Scholar 

  25. Guthrie OW (2008) Aminoglycoside induced ototoxicity. Toxicology 249:91–96

    Article  PubMed  Google Scholar 

  26. Henderson D, Bielefeld EC, Harris KC, Bu BH (2006) The role of oxidative stress in noise-induced hearing loss. Ear Hear 27:1–19

    Article  PubMed  Google Scholar 

  27. Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V (2007) Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Res 226:157–167

    Article  PubMed  CAS  Google Scholar 

  28. Rybak LP, Mukherjea D, Jajoo S, Ramkumar V (2009) Cisplatin ototoxicity and protection: clinical and experimental studies. Tohoku J Exp JMed 219:177–186

    Article  CAS  Google Scholar 

  29. Videhult P, Laurell G, Wallin I, Ehrsson H (2006) Kinetics of cisplatin and its monohydrated complex with sulfur-containing compounds designed for local otoprotective administration. Exp Biol Med (Maywood) 231:1638–1645

    CAS  Google Scholar 

  30. Mukherjea D, Whitworth CA, Nandish S, Dunaway G, Rybak LP, Ramkumar V (2006) Expression of the kidney injury molecule 1 in the rat cochlea and induction by cisplatin. Neuroscience 139:733–740

    Article  PubMed  CAS  Google Scholar 

  31. Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, Muniappa N, Thudium D, Gerhold D, Holder DJ, Bobadilla NA, Marrer E, Perentes E, Cordier A, Vonderscher J, Maurer G, Goering PL, Sistare PL, Bonventre JV (2010) Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol 28:478–485

    Article  PubMed  CAS  Google Scholar 

  32. Mukherjea D, Jajoo S, Kaur T, Sheehan KE, Ramkumar V, Rybak LP (2010) Transtympanic administration of short interfering (si)RNA for the NOX3 isoform of NADPH oxidase protects against cisplatin-induced hearing loss in the rat. Antioxid Redox Signal 13:589–598

    Article  PubMed  CAS  Google Scholar 

  33. Mukherjea D, Jajoo S, Whitworth C, Bunch JR, Turner JG, Rybak LP, Ramkumar V (2008) Short interfering RNA against transient receptor potential vanilloid 1 attenuates cisplatin-induced hearing loss in the rat. J Neurosci 28:13056–13065

    Article  PubMed  CAS  Google Scholar 

  34. Bus JS, Gibson JE (1984) Paraquat: model for oxidant-initiated toxicity. Environ Health Perspect 55:37–46

    Article  PubMed  CAS  Google Scholar 

  35. Cristóvão AC, Choi DH, Baltazar G, Beal MF, Kim YS (2009) The role of NADPH oxidase 1-derived reactive oxygen species in paraquat-mediated dopaminergic cell death. Antioxid Redox Signal 11:2105–2118

    Article  PubMed  Google Scholar 

  36. Bielefeld EC, Hu BH, Harris KC, Henderson D (2005) Damage and threshold shift resulting from cochlear exposure to paraquat-generated superoxide. Hear Res 207:35–42

    Article  PubMed  CAS  Google Scholar 

  37. Nicotera TM, Ding D, McFadden SL, Salvemini D, Salvi R (2004) Paraquat-induced hair cell damage and protection with the superoxide dismutase mimetic m40403. Audiol Neurootol 9:353–362

    Article  PubMed  CAS  Google Scholar 

  38. Mukherjea D, Jajoo S, Sheehan K, Kaur T, Sheth S, Bunch J, Perro C, Rybak LP, Ramkumar V (2011) NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss. Antioxid Redox Signal 14:999–1010

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are supported by grants from the National Institutes of Health (NIH), the National Institute for Deafness and other Communicative Disorders (NIDCD) grant R01-DC 02396 (L.P.R.) and F32 DC 009950 (D.M.).

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Authors and Affiliations

  1. Department of Surgery, Division of Otolaryngology, Southern Illinois University, School of Medicine, 747 N. Rutledge Street, PO Box 19649, Springfield, IL, 62794-9649, USA

    Leonard P. Rybak & Debashree Mukherjea

  2. Division of Otolaryngology, Department of Pharmacology, Southern Illinois University, School of Medicine, PO Box 19649, Springfield, IL, 62794-9649, USA

    Sarvesh Jajoo, Tejbeer Kaur & Vickram Ramkumar

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  1. Leonard P. Rybak
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  2. Debashree Mukherjea
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  3. Sarvesh Jajoo
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  4. Tejbeer Kaur
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  5. Vickram Ramkumar
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Correspondence to Leonard P. Rybak.

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Rybak, L.P., Mukherjea, D., Jajoo, S. et al. siRNA-mediated knock-down of NOX3: therapy for hearing loss?. Cell. Mol. Life Sci. 69, 2429–2434 (2012). https://doi.org/10.1007/s00018-012-1016-3

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  • DOI: https://doi.org/10.1007/s00018-012-1016-3

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