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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC002396-18A1
Application #
8697871
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
1994-07-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
18
Fiscal Year
2014
Total Cost
$310,062
Indirect Cost
$97,562
Name
Southern Illinois University School of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
038415006
City
Springfield
State
IL
Country
United States
Zip Code
62794
Jiang, Peng; Ray, Amrita; Rybak, Leonard P et al. (2016) Role of STAT1 and Oxidative Stress in Gentamicin-Induced Hair Cell Death in Organ of Corti. Otol Neurotol 37:1449-56
Kaur, Tejbeer; Borse, Vikrant; Sheth, Sandeep et al. (2016) Adenosine A1 Receptor Protects Against Cisplatin Ototoxicity by Suppressing the NOX3/STAT1 Inflammatory Pathway in the Cochlea. J Neurosci 36:3962-77
Mukherjea, Debashree; Ghosh, Sumana; Bhatta, Puspanjali et al. (2015) Early investigational drugs for hearing loss. Expert Opin Investig Drugs 24:201-17
Sheth, Sandeep; Brito, Rafael; Mukherjea, Debashree et al. (2014) Adenosine receptors: expression, function and regulation. Int J Mol Sci 15:2024-52
Brito, Rafael; Sheth, Sandeep; Mukherjea, Debashree et al. (2014) TRPV1: A Potential Drug Target for Treating Various Diseases. Cells 3:517-45
Jajoo, Sarvesh; Mukherjea, Debashree; Kaur, Tejbeer et al. (2013) Essential role of NADPH oxidase-dependent reactive oxygen species generation in regulating microRNA-21 expression and function in prostate cancer. Antioxid Redox Signal 19:1863-76
Schacht, Jochen; Talaska, Andra E; Rybak, Leonard P (2012) Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention. Anat Rec (Hoboken) 295:1837-50
Rybak, Leonard P; Mukherjea, Debashree; Jajoo, Sarvesh et al. (2012) siRNA-mediated knock-down of NOX3: therapy for hearing loss? Cell Mol Life Sci 69:2429-34
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
Mukherjea, Debashree; Rybak, Leonard P; Sheehan, Kelly E et al. (2011) The design and screening of drugs to prevent acquired sensorineural hearing loss. Expert Opin Drug Discov 6:491-505

Showing the most recent 10 out of 46 publications