Ototoxicity is a common side effect of cisplatin, a drug widely used for the treatment of a various solid tumor. Cisplatin ototoxicity is irreversible and is especially traumatic for the pediatric population since it hampers their communication skills and social development. Cisplatin is unique among platinum-based chemotherapy by having a broad spectrum of activity against a number of different cancers compared to more limited activity for carboplatin and oxaliplatin. The continued clinical use of cisplatin suggests ototoxicity will continue to be a problem unless a substantial effort is undertaken to develop effective otoprotective therapies. One current treatment strategy uses antioxidants to decrease reactive oxygen species (ROS), which has been implicated in cisplatin ototoxicity. While this approach provides otoprotection, there are concerns that antioxidants could limit the efficacy of cisplatin. Other treatment approaches target proteins involved in apoptosis which contribute to death of outer hair cells (OHCs). However, inhibition of caspases, p53, or activation of DNA repair enzymes may promote the development of tumors or promote tumor chemoresistance. A more rational approach should target the source of ROS generation or downstream signaling molecules which are not linked to oncogenesis and utilize localize (intra-tympanic) delivery of otoprotective agents. We have identified two such molecules, namely the NADPH oxidase isoform, NOX3 (a major source of ROS generation in the cochlea) and transient receptor potential vanilloid 1 channel (implicated in cisplatin ototoxicity). Knockdown of these proteins reduced damage to OHCs and reduced hearing loss induced by cisplatin. Recent findings from our laboratories indicate that TRPV1 and NOX3 can increase the activity of signal transducers and activators of transcription (STAT1), an important mediator of inflammation. Knockdown of STAT1 reduced the expression of inflammatory genes (such as TNF-a) and protected against cisplatin-induced hearing loss. This has led to the hypothesis that inflammation is a significant component of cisplatin-induced ototoxicity. Furthermore, we proposed that STAT1 is a downstream target of NOX3 and TRPV1 and thereby represents a novel target for otoprotective drugs. The overall goal of this project is to examine a role of STAT1 in cisplatin ototoxicity and determine whether it represents a viable target for otoprotective therapies. Specifically, we will (1) determine the mechanism(s) underlying ROS activation of STAT1, (2) characterize in more detail the ability of intra-tympanic injection of STAT1 siRNA to inhibit cisplatin-induced hearing loss, (3) determine the expression profile of inflammatory genes induced by cisplatin and (4) to determine whether intra-tympanic injection of a selective inhibitor of TNF-a (etanercept) protects against cisplatin ototoxicity. Overall, the data obtained from this study would expand our understanding of STAT1 activation in the cochlea and provide the rationale for targeting this transcription factor for combating cisplatin ototoxicity and other forms of hearing loss. Our findings are expected to have direct translational application to the treatment of hearing loss in cancer patients.

Public Health Relevance

The current research proposal focuses on hearing loss observed clinically in patients being treated with the anticancer drug, cisplatin. Research from our laboratory indicates that cisplatin produces inflammation in the inner ear and this leads to death of cells responsible for transmission of sound in the inner ear. We will test the ability of anti-inflammatory agents to protect against cisplatin-mediated hearing loss when administered directly through the ear drum. We believe the information gained from this study will lead to potentially new treatments for treating hearing loss.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-IFCN-B (02))
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Freeman, Nancy
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Southern Illinois University School of Medicine
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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
Brito, Rafael; Sheth, Sandeep; Mukherjea, Debashree et al. (2014) TRPV1: A Potential Drug Target for Treating Various Diseases. Cells 3:517-45
Sheth, Sandeep; Brito, Rafael; Mukherjea, Debashree et al. (2014) Adenosine receptors: expression, function and regulation. Int J Mol Sci 15:2024-52
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