Epigallocatechin-3-gallate, a prototypic chemopreventative agent for protection against cisplatin-based ototoxicity

Abstract

Cisplatin-induced ototoxicity is one of the major factors limiting cisplatin chemotherapy. Ototoxicity results from damage to outer hair cells (OHCs) and other regions of the cochlea. At the cellular level, cisplatin increases reactive oxygen species (ROS) leading to cochlear inflammation and apoptosis. Thus, ideal otoprotective drugs should target oxidative stress and inflammatory mechanisms without interfering with cisplatin's chemotherapeutic efficacy. In this study, we show that epigallocatechin-3-gallate (EGCG) is a prototypic agent exhibiting these properties of an effect otoprotective agent. Rats administered oral EGCG demonstrate reduced cisplatin-induced hearing loss, reduced loss of OHCs in the basal region of the cochlea and reduced oxidative stress and apoptotic markers. EGCG also protected against the loss of ribbon synapses associated with inner hair cells and Na+/K+ ATPase α1 in the stria vascularis and spiral ligament. In vitro studies showed that EGCG reduced cisplatin-induced ROS generation and ERK1/2 and signal transducer and activator of transcription-1 (STAT1) activity, but preserved the activity of STAT3 and Bcl-xL. The increase in STAT3/STAT1 ratio appears critical for mediating its otoprotection. EGCG did not alter cisplatin-induced apoptosis of human-derived cancer cells or cisplatin antitumor efficacy in a xenograft tumor model in mice because of its inability to rescue the downregulation of STAT3 in these cells. These data suggest that EGCG is an ideal otoprotective agent for treating cisplatin-induced hearing loss without compromising its antitumor efficacy.

Mechanisms of Cisplatin-Induced Ototoxicity and Prevention

“…43 An extract from green tea epigallocatechin-3gallate (EGCG) was shown to protect against cisplatin ototoxicity in the rat and tumor-bearing mouse without interference with the tumor killing efficacy of cisplatin. 15 EGCG protected against cisplatin-induced hair cell damage, ABR threshold shifts, and prevented a decrease in the strial Na/K-ATPase activity. 15 Intratympanic application of siRNAs against TRPV1, NOX3, and STAT1 provided protection against cisplatin ototoxicity in rat model by decreasing ROS generation and preventing inflammation in the cochlea.…”

“…15 EGCG protected against cisplatin-induced hair cell damage, ABR threshold shifts, and prevented a decrease in the strial Na/K-ATPase activity. 15 Intratympanic application of siRNAs against TRPV1, NOX3, and STAT1 provided protection against cisplatin ototoxicity in rat model by decreasing ROS generation and preventing inflammation in the cochlea. 19 A novel compound was recently reported to ameliorate cisplatin ototoxicity in rodents.…”

“…14 A recent study reported that rats treated with cisplatin showed a significant reduction in the average number of synaptic ribbons on each inner hair cell (IHC) in the basal and middle, but not in the apical turn by means of the synaptic marker, C-terminal binding protein 2 (CtBP2). 15…”

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

“…administered EGCG mitigated cisplatin-induced hearing loss along with a marked reduction in the loss of outer hair cells in the basal cochlear region. Importantly, chemotherapeutic drug-induced toxicity was also reduced mainly though suppression of apoptotic markers and oxidative stress [14] It has recently been reported that IFNγ-mediated PD-L1 levels were noted to be downregulated after treatment with green tea extracts and EGCG mainly through inhibition of JAK2/STAT1 signaling in A549 cells [15]. Likewise, EGF-stimulated PD-L1 upregulation was reduced in EGCG-treated Lu99 cells by inactivation of EGFR/AKT transduction cascade.…”

“…Orally administered EGCG mitigated cisplatin-induced hearing loss along with a marked reduction in the loss of outer hair cells in the basal cochlear region. Importantly, chemotherapeutic drug-induced toxicity was also reduced mainly though suppression of apoptotic markers and oxidative stress [14].…”