Trichostatin A reduces cisplatin-induced ototoxicity through the STAT6 signaling pathway

Abstract

Cisplatin-induced ototoxicity limits its wide application in the treatment of cancer. A number of pro-inflammatory factors have been shown to be involved in cisplatin-induced ototoxicity. Trichostatin A (TSA) is an anti-inflammatory agent that has been shown to exert protective effects against cisplatin-induced ototoxicity. In the present study, we hypothesized that TSA may protect cochlear hair cells from cisplatin-induced damage by regulating the interleukin (IL)-4/signal transducer and activator of transcription (STAT)6 signaling pathway. Wistar rat cochlear explants were cultured in DMEM. The differentially expressed genes of the basilar membrane were identified by microarray analysis of global expression profiles. Hair cells were stained with rhodamine phalloidin and observed under a scanning electron microscope to evaluate the protective effects of TSA against cisplatin-induced cochlear hair cell damage. The levels of cytokines in the supernatant of the cultured basilar membranes was measured using ELISA. STAT6 and phosphorylated (p-)STAT6 expression was measured by western blot analysis. Morphological observation revealed that cisplatin induced the disarrangement of the cochlear hair cells, as well as the fusion and detachment of the cilia, while these aberrant alterations were inhibited by TSA, suggesting that TSA exerts a protective effect against cisplatin-induced damage to hair cells. Furthermore, the increase in the expression of STAT6 and p-STAT6 induced by cisplatin was reversed by treatment with TSA, accompanied by the decreased expression of IL-1β, IL-4 and IL-6. Therefore, our data demonstrate that TSA reduces cisplatin-induced ototoxicity by inhibiting pro-inflammatory factor-mediated STAT6 signaling. Thus, TSA may be used to prevent the side-effects associated with the use of cisplatin in cancer treatment.

Histone deacetylase inhibition prevents cell death induced by loss of tricellular tight junction proteins in temperature-sensitive mouse cochlear cells

“…iHDACs are also known to reduced noise-, gentamicin-, and cisplatin-induced ototoxicity [ 15 , 16 , 17 , 26 ]; however, the mechanism by which this occurs remains unclear. In the present study, iHDAC treatment increased both TRIC and LSR expression.…”

“…Mutations in the gene encoding TRIC are responsible for autosomal recessive nonsyndromic hearing loss [ 9 , 10 ], which was determined to result from a loss in mechanosensory cochlear cells in transgenic mouse studies [ 27 ]. Significantly, disruption of the strands of intramembrane particles connecting bicellular and tricellular junctions may affect the paracellular permeability of ions or small molecules, creating a toxic microenvironment for cochlear cells [ 26 ]. On the other hand, recent report indicates that LSR regulates TRIC recruitment to tTJs [ 5 ].…”

“…HDACs have a crucial role in both, transcription regulation and protein modification [ 30 ]. Previous studies have identified iHDACs as a promising strategy for therapeutic intervention in cancer, neurological disorders, immune disorders31, and hearing loss [ 15 , 16 , 17 , 26 ]. The deacetylation of histone core proteins may trigger cell death; thus, iHDACs could function to attenuate the apoptotic-signaling pathways involved in noise-induced hearing loss [ 15 , 16 ].…”

“…The present study used TSA and iHDAC6 as iHDACs. TSA is an anti-inflammatory agent derived from streptavidin metabolites and reduces cisplatin-induced ototoxicity by regulating the IL-4/STAT6 signaling pathway [ 26 ]. In addition, TSA leads to a prolonged NF-κB activation and a subsequent increase in the pro-inflammatory response [ 31 ].…”

Acquired sensorineural hearing loss in children: current research and therapeutic perspectives

“…Other protective drugs have been experimented in animal and human studies during the past few years; these include alpha-lipoic acid 61 , trichostatin A 62 , oxytocin 63 , resveratol 64 , hesperetin 65 and lutein 66 . However, data are preliminary and have not been confirmed.…”