Date of Award

12-1-2017

Degree Name

Doctor of Philosophy

Department

Pharmacology

First Advisor

Ramkumar, Vickram

Abstract

Cisplatin is a commonly used chemotherapeutic agent for multiple solid tumors. However, cisplatin-induced neurotoxicity, nephrotoxicity and hearing loss hamper its use in clinical setting. Although, neurotoxicity and nephrotoxicity can be prevented, there is no cure for cisplatin-induced hearing loss. Cisplatin-induced hearing loss results from damage to outer hair cells (OHCs) in basal turn of the cochlea, to spiral ganglion neurons (SGN), stria vascularis (SV) and fibrocytes of spiral ligament (SL). At the cellular level, cisplatin produces profound increases in reactive oxygen species (ROS) that stimulate cell signaling pathways leading to cochlear inflammation, apoptosis and permanent hearing loss. Thus, potential otoprotective drugs should target oxidative stress and inflammatory mechanisms without interfering with cisplatin chemotherapeutic efficacy. In this study, I characterized the otoprotective actions of the green tea extract, epigallocatechin 3-gallate (EGCG), which possesses anti-oxidant, anti-inflammatory and anti-tumor properties. Oral administration of EGCG to male Wistar rats reduced cisplatin-induced hearing loss, assessed by auditory brainstem responses. These changes were associated with a reduction in cisplatin-induced loss of OHCs primarily in the basal region of the cochlea, along with reduced oxidative stress, inflammatory and apoptotic markers. In addition, EGCG protected against cisplatin-induced decrease in inner hair cell (IHCs) ribbon synapses, labeled with CtBP2. EGCG also protected against cisplatin-induced loss of Na+/K+ ATPase α1 immunoreactivity in the stria vascularis and spiral ligament. In vitro studies using University Bristol/Organ of Corti-1 (UB/OC-1) cells showed that EGCG reduced cisplatin-induced ROS generation and the activation of ERK and STAT1, while it preserved the activity of STAT3 and levels of Bcl-xL. Moreover, EGCG suppressed oxidative stress, inflammatory and apoptotic markers in cisplatin-treated UB/OC-1 cells. Co-administration of EGCG did not alter cisplatin-induced apoptosis of human-derived head and neck cancer cells, ovarian cancer cells or colon cancer cells. In studies using a xenograft model of head and neck cancer in severe combined immunodeficient (SCID) mice, I showed that EGCG did not interfere with cisplatin chemotherapeutic efficacy. These data suggest that EGCG is a potential otoprotective agent for treating cisplatin-induced hearing loss without compromising its chemotherapeutic efficacy.

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