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.
Highlights
Authors Vikrant Borse, Raheem FH Al Aameri, Kelly Sheehan, Sandeep Sheth, Tejbeer Kaur, Debashree Mukherjea, Srinivasan Tupal, Michelle Lowy, Sumana Ghosh, Asmita Dhukhwa, Puspanjali Bhatta, Leonard P
~ 41% lactate dehydrogenase (LDH) release observed at 50 μM EGCG (~41% reduction), with maximal response obtained at 150 μM EGCG (Figure 1b)
No significant loss of outer hair cells (OHCs) in the middle and apical turns of cochlea induced by cisplatin was seen, in spite of distinct hearing loss observed with cisplatin at lower to middle frequencies (Figure 1h)
Summary
Authors Vikrant Borse, Raheem FH Al Aameri, Kelly Sheehan, Sandeep Sheth, Tejbeer Kaur, Debashree Mukherjea, Srinivasan Tupal, Michelle Lowy, Sumana Ghosh, Asmita Dhukhwa, Puspanjali Bhatta, Leonard P. The generation of reactive oxygen species (ROS) has long been recognized as an important contributor to cisplatininduced hearing loss.[10,11,12,13,14] Antioxidants showed good promise initially for treating cisplatin-induced hearing loss, but concerns that these agents could inhibit cisplatin’s chemotherapeutic efficacy[15] have reduced interest in developing antioxidants as otoprotectants. Recent studies have shown that cisplatin activates the mitogen-activated kinase (MAPK) pathway, linked to downstream targets such as signal transducer and activator of transcription-1 (STAT1) and p53 activation. This cascade leads to inflammation and apoptosis of OHCs and hearing loss.[16,17,18,19,20,21] STAT1 contributes to a drugresistant phenotype in a number of cancers. Epigallocatechin-3-gallate (EGCG) is an abundant polyphenol in green tea extract, which possesses antioxidant, antiinflammatory and antitumorigenic properties,[22,23,24,25,26] and a known inhibitor of STAT1.21,27 Studies have shown beneficial effects of EGCG in treating diabetes, cancer, neurodegenerative disorders, cardiovascular disease and obesity.[28,29,30,31] Our interest in EGCG stems from the fact that it provides an orally effective STAT1 inhibitor with anticancer properties, which could complement the overall therapeutic benefits of cisplatin
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