Cisplatin is a critical component of current chemotherapy regimens. Unfortunately, cisplatin frequently causes ototoxicity that is bilateral and irreversible. This is particularly challenging in young children in whom hearing loss severely hampers speech, cognitive and social development. Thus, there is an urgent need for new drugs to reduce cisplatin ototoxicity. Recent studies from our laboratory have shown that a single transtympanic injection of capsaicin (TRPV1 agonist) produced transient hearing loss and temporary increases in inflammatory cytokines. Surprisingly, pretreatment with transtympanic capsaicin alleviated cisplatin ototoxicity. Preliminary data show that oral capsaicin also reduces cisplatin-induced auditory brain stem response (ABER) threshold shifts. Our in vitro studies suggest that capsaicin's "preconditioning" effect results from transient STAT1 up-regulation. Activation of STAT1 by capsaicin may modify or sequester STAT1, preventing its interaction with p53 when cochlear cells are subsequently challenged by cisplatin. Alternatively, capsaicin could activate STAT1 (i.e. increase its phosphorylation) differently from cisplatin. Capsaicin could also activate cytoprotective STAT proteins (such as STAT3). Capsaicin can also increase cannabinoid (CB) expression in the cochlea, which can be cytoprotective. Preliminary experiments in UB/OC1 cells show that capsaicin up-regulates CB receptors in these cells. Experiments in aim1 should confirm the efficacy of oral capsaicin against cisplatin ototoxicity and the subsequent 3 aims will elucidate mechanisms of protection.
Aim 2 will determine the molecular basis of capsaicin-mediated protection against cisplatin ototoxicity. The hypothesis is that capsaicin activates STAT1 (by mediating Ser727 and Tyr701 phosphorylation) which sequesters (or down-regulates) it, thereby decreasing the availability of STAT1 accessible for activation by cisplatin.
Aim 3 will test the hypothesis that capsaicin-mediated protection against cisplatin ototoxicity by activation, or increasing the expression, of CB receptors in the cochlea. CB activation reduces cisplatin ototoxicity in vitro and has demonstrated anti-inflammatory and neuroprotective effects in numerous reports.
Aim 4 will test the hypothesis that Gene Array will demonstrate changes in genes of interest in the cochlea of rats treated with capsaicin, cisplatin and cisplatin plus capsaicin.
Aim 5 will determine whether capsaicin interferes with or actually enhances the antitumor efficacy of cisplatin. This research will offer great promise to provide novel protective oral treatments to ameliorate cisplatin ototoxicity.

Public Health Relevance

Cisplatin is an important drug for the treatment of cancer. Unfortunately, cisplatin frequently causes irreversible hearing loss in both ears. This is particularly challenging in young children in whom hearing loss severely hampers speech, cognitive and social development. Thus, there is an urgent need for new drugs to prevent hearing loss while preserving the ability of cisplatin to treat cancer. The experiments proposed in this research proposal will expand our findings that an extract from hot peppers, capsaicin, reduces hearing loss and inner ear damage caused by cisplatin in animal experiments. Capsaicin promises to be an exciting new treatment to prevent hearing loss from cisplatin in cancer patients.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
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Auditory System Study Section (AUD)
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Freeman, Nancy
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Southern Illinois University School of Medicine
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Sheth, Sandeep; Brito, Rafael; Mukherjea, Debashree et al. (2014) Adenosine receptors: expression, function and regulation. Int J Mol Sci 15:2024-52
Mukherjea, Debashree; Rybak, Leonard P (2011) Pharmacogenomics of cisplatin-induced ototoxicity. Pharmacogenomics 12:1039-50
Mukherjea, Debashree; Jajoo, Sarvesh; Sheehan, Kelly et al. (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
Kaur, T; Mukherjea, D; Sheehan, K et al. (2011) Short interfering RNA against STAT1 attenuates cisplatin-induced ototoxicity in the rat by suppressing inflammation. Cell Death Dis 2:e180
Mukherjea, Debashree; Jajoo, Sarvesh; Kaur, Tejbeer et al. (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 13:589-98
Rybak, Leonard P; Mukherjea, Debashree; Jajoo, Sarvesh et al. (2009) Cisplatin ototoxicity and protection: clinical and experimental studies. Tohoku J Exp Med 219:177-86
Mukherjea, Debashree; Jajoo, Sarvesh; Whitworth, Craig et al. (2008) Short interfering RNA against transient receptor potential vanilloid 1 attenuates cisplatin-induced hearing loss in the rat. J Neurosci 28:13056-65
Pingle, Sandeep C; Jajoo, Sarvesh; Mukherjea, Debashree et al. (2007) Activation of the adenosine A1 receptor inhibits HIV-1 tat-induced apoptosis by reducing nuclear factor-kappaB activation and inducible nitric-oxide synthase. Mol Pharmacol 72:856-67
Rybak, Leonard P (2007) Mechanisms of cisplatin ototoxicity and progress in otoprotection. Curr Opin Otolaryngol Head Neck Surg 15:364-9
Rybak, L P; Ramkumar, V (2007) Ototoxicity. Kidney Int 72:931-5

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