Supporting Cells and Their Potential Roles in Cisplatin-Induced Ototoxicity

Abstract

Cisplatin is a known ototoxic chemotherapy drug, causing irreversible hearing loss. Evidence has shown that cisplatin causes inner ear damage as a result of adduct formation, a proinflammatory environment and the generation of reactive oxygen species within the inner ear. The main cochlear targets for cisplatin are commonly known to be the outer hair cells, the stria vascularis and the spiral ganglion neurons. Further evidence has shown that certain transporters can mediate cisplatin influx into the inner ear cells including organic cation transporter 2 (OCT2) and the copper transporter Ctr1. However, the expression profiles for these transporters within inner ear cells are not consistent in the literature, and expression of OCT2 and Ctr1 has also been observed in supporting cells. Organ of Corti supporting cells are essential for hair cell activity and survival. Special interest has been devoted to gap junction expression by these cells as certain mutations have been linked to hearing loss. Interestingly, cisplatin appears to affect connexin expression in the inner ear. While investigations regarding cisplatin-induced hearing loss have been focused mainly on the known targets previously mentioned, the role of supporting cells for cisplatin-induced ototoxicity has been overlooked. In this mini review, we discuss the implications of supporting cells expressing OCT2 and Ctr1 as well as the potential role of gap junctions in cisplatin-induced cytotoxicity.

Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI

“…[8][9][10] Cisplatin buildup in the inner ear causes hair cell death and damage to the supporting cells, neuron fibers, and stria vascularis cells. 7,11,12 Despite its potent antitumor effect, the clinical use of cisplatin is doselimited by nephrotoxicity, which is commonly manifested as AKI or chronic renal dysfunction. [13][14][15][16][17] The renal function impairment can be progressive and eventually lead to CKD.…”

Diabetes Mellitus and Hearing Loss: A Complex Relationship

“…Although they are not the actual sound transducers, supporting cells are essential, and without them, hearing would not be possible. There are approximately 15 supporting cells per each IHC, and the different types of supporting cells include: border, inner phalangeal, pillar, Deiters’ (outer phalangeal cells), and Hensen’s cells [ 36 ]. The basilar membrane (BM) is an extracellular matrix that separates the scala media from the scala tympani and vibrates in response to sound-induced pressure changes in the cochlear fluids.…”

FDA-Approved MEK1/2 Inhibitor, Trametinib, Protects Mice from Cisplatin and Noise-Induced Hearing Loss

“…Additionally, MAPK activation has been demonstrated to occur in the supporting cells of the inner ear following cisplatin administration and noise exposure, specifically in the Deiters' and inner phalangeal cells, and these supporting cells help clear glutamate from the synapses between hair cells and the nerve fibers [24][25][26]. Lowering MAPK activity in the supporting cells could be helping with supporting cell health which would allow for proper functioning of these cell types, such as clearing out glutamate from the synapses [59][60][61]. Glutamate excitotoxicity is known to occur following both cisplatin and noise exposure and this leads to synaptic dysfunction and cell death [62,63].…”

“…Glutamate excitotoxicity is known to occur following both cisplatin and noise exposure and this leads to synaptic dysfunction and cell death [62,63]. Preventing supporting cell dysfunction and death could help clear glutamate out of the synapses which would reduce the synaptopathy that occurs from these ototoxic insults [59,61]. This is a very interesting mechanism that MAPK inhibition is protecting from hearing loss through, and further research is needed to elucidate exactly how this is occurring.…”