Mechanisms of Cisplatin-Induced Ototoxicity and Prevention

Abstract

Cisplatin is a highly effective antineoplastic agent used to treat solid tumors. Unfortunately, the administration of this drug leads to significant side effects, including ototoxicity, nephrotoxicity, and neurotoxicity. This review addresses the mechanisms of cisplatin-induced ototoxicity and various strategies tested to prevent this distressing adverse effect. The molecular pathways underlying cisplatin ototoxicity are still being investigated. Cisplatin enters targeted cells in the cochlea through the action of several transporters. Once it enters the cochlea, cisplatin is retained for months to years. It can cause DNA damage, inhibit protein synthesis, and generate reactive oxygen species that can lead to inflammation and apoptosis of outer hair cells, resulting in permanent hearing loss. Strategies to prevent cisplatin ototoxicity have utilized antioxidants, transport inhibitors, G-protein receptor agonists, and anti-inflammatory agents. There are no FDA-approved drugs to prevent cisplatin ototoxicity. It is critical that potential protective agents do not interfere with the antitumor efficacy of cisplatin.

Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity

“…Historically, both ex vivo and in vivo studies have provided important insights into the mechanisms underlying hair cell death pathways (Wu et al, 2001; Wang et al, 2004; Rybak, 2007; Rybak et al, 2007; Guthrie, 2008; Warchol, 2010; Ding et al, 2011; Schacht et al, 2012; Francis et al, 2013; Nicholas et al, 2017). The conclusions, however, differ significantly between the ex vivo and in vivo context, and thus have created confusion in the ototoxicity field.…”

The role of peroxiredoxin I in cisplatin-induced ototoxicity

“…Cisplatin is associated with increased oxidative stress and post-translational changes in the components of the apoptotic pathways [12,13]. Stress-activated protein kinases are critical components of this intracellular signaling network [20].…”

“…Of these, ototoxicity is one of the most serious concerns because of the risk of permanent hearing loss associated with cochlear damage. The ototoxic mechanisms of cisplatin have gradually been identified, and oxidative stress has been implied as one of the main pathophysiologies [12,13]. In vitro experiments showed that cisplatin raises ROS levels and depletes the intracellular concentration of glutathione [14].…”

Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis

“…Insight into these ion homeostatic mechanisms may be important to understanding their functional contribution to hearing and hearing loss (Nickel & Forge, 2008;Zdebik, Wangemann, & Jentsch, 2009). These gene regulatory networks within the unperturbed wild type adult mouse SV establish a basis for identifying and interpreting changes in these networks in disease settings including, but not limited to, Meniere's disease (Collin et al, 2008;Ishiyama, Tokita, Lopez, Tang, & Ishiyama, 2007;Kariya et al, 2009), autoimmune inner ear disease (Calzada, Balaker, Ishiyama, Lopez, & Ishiyama, 2012), cisplatin-induced hearing loss (Breglio et al, 2017;Rybak, Mukherjea, & Ramkumar, 2019), and enlarged vestibular aqueduct syndrome (T. Ito, Nishio, Wangemann, & Griffith, 2015;Miyagawa et al, 2014).…”