Gstm1/Gstt1 is essential for reducing cisplatin ototoxicity in CBA/CaJ mice

Abstract

Cisplatin is a widely used chemotherapeutic agent. However, its clinical utility is limited because of cisplatin‐induced ototoxicity. Glutathione S‐transferase (GST) was found to play a vital role in reducing cisplatin ototoxicity in mice. Deletion polymorphisms of GSTM1 and GSTT1, members of the GST family, are common in humans and are presumed to be associated with cisplatin‐induced hearing impairment. However, the specific roles of GSTM1 and GSTT1 in cisplatin ototoxicity are not completely clear. Here, under cisplatin treatment, simultaneous deletion of Gstm1 and Gstt1 lead to a more profound hearing loss in CBA/CaJ mice (Gstm1/Gstt1‐DKO) than in wild‐type mice. The Gstm1/Gstt1‐DKO mice, in which phase II detoxification genes were upregulated, exhibited more severe oxidative stress and higher outer hair cell apoptosis in the cochleae than the control mice. Thus, our study revealed that Gstm1 and Gstt1 protect auditory hair cells from cisplatin‐induced ototoxicity in the CBA/CaJ mice, and genetic screening for GSTM1 and GSTT1 polymorphisms could help determine a standard cisplatin dose for cancer patients undergoing chemotherapy.

Cisplatin ototoxicity mechanism and antagonistic intervention strategy: a scope review

“…And the loss eventually changes antioxidant capacity and increases oxidative DNA and protein damage in the cochlea of cisplatin-treated Gstm1/Gstt1-DKO mice. Therefore, the presence of glutathione s-transferase mu 1 (Gstm1/Gstt1) genes is crucial for CBA/CaJ mice to resist cisplatin-induced ototoxicity ( Li et al, 2022c ). The overexpression of Wnt signaling in spiral ganglion neuron (SGNs) leads to increased expression of tumor protein P53-induced glycolysis and apoptosis regulator (TIGAR) and decreased levels of ROS, thereby preventing the apoptotic efflux of cascade amplification reaction ( Liu et al, 2019b ).…”