The Mechanotransduction Channel and Organic Cation Transporter Are Critical for Cisplatin Ototoxicity in Murine Hair Cells

Abstract

Cisplatin is one of the most widely used chemotherapeutic drugs across the world. However, the serious ototoxic effects, leading to permanent hair cell death and hearing loss, significantly limit the utility of cisplatin. In zebrafish, the functional mechanotransduction channel is required for cisplatin ototoxicity. However, it is still unclear the extent to which the mechanotransduction channel is involved in cisplatin uptake and ototoxicity in mammalian hair cells. Herein, we show that genetically disrupting mechanotransduction in mouse partially protects hair cells from cisplatin-induced hair cell death. Using a fluorescent-dye conjugated cisplatin, we monitored cisplatin uptake in cochlear explants and found that functional mechanotransduction is required for the uptake of cisplatin in murine hair cells. In addition, cimetidine, an inhibitor of the organic cation transporter, also partially protects hair cells from cisplatin ototoxicity. Notably, the otoprotective effects of cimetidine do not require mechanotransduction. These findings suggest that both the mechanotransduction channel and the organic cation transporter are critical for cisplatin ototoxicity in murine hair cells.

Otoprotection against aminoglycoside- and cisplatin-induced ototoxicity focusing on the upstream drug uptake pathway

“…22 One of the primary routes of cisplatin into the hair cells is through the transport of OCT-2 and CTR-1, which are highly expressed in the stria vascularis and cochlear hair cells. [34][35][36] Additionally, cisplatin can enter the hair cell membranes via passive diffusion. 22 Fig.…”

“…Blocking certain transporters and MET channels in hair cells have also been demonstrated to reduce cisplatininduced ototoxicity. [34][35][36] Both the entry of AGs and cisplatin into the hair cells share a common pathway, that is, the MET channel. 32,50 Therefore, recent efforts in this field have resulted in the identification of competitive blockers of MET to prevent AG-and cisplatininduced ototoxicity.…”

“…Prevents hearing loss at click stimulus and 8, 16, and 32 kHz frequencies when administered intratympanically before cisplatin. Mice Cimetidine 35,36 Cisplatin Block OCT. Mice Reduces ABR threshold shifts at 16 and 32 KHz. which binds near the apical membrane of the strial marginal cells, but not in the cochlear hair cells.…”

“…35,36 However, recent studies have indicated that blocking MET and OCT-2 alone may not provide complete protection against cisplatin, suggesting that an additional entry route should be targeted. 36 These findings suggest that a combination of drugs that target multiple entry routes may be needed to provide complete protection against cisplatin-induced ototoxicity. Generally, MET channel blockers appear to be a promising option for protection against hearing loss caused by both AG and cisplatin in clinical settings.…”

Hair cell toxicology: With the help of a little fish

“…Using a fluorescently-labeled cisplatin analog (Rho-Pt) in zebrafish larvae, and a mix of pharmacological and genetic tools to inhibit mechanotransduction in hair cells, it was demonstrated that the mechanotransduction channel (MET) is required for cisplatin uptake and death of hair cells (Thomas et al, 2013). Recently, this has been proved the case also in mice; cochlear explants from mice lacking Tmie (one of the proteins that form the mechanotransduction channel) are partially resistant to cisplatin treatment and Oct2 inhibition further increase their protection (Li et al, 2022).…”