Introduction

About 430 million people have moderate to severe hearing impairments and according to the World Health Organization that number will keep increasing (WHO, 2021). Hearing loss can occur from several things: age, exposure to loud sound, hereditary illnesses, and some medications. Certain medications can damage the ear which can result in hearing loss. These medications are ototoxic. Currently, FDA approved drugs are not tested for ototoxicity.

There are different classes of therapeutic agents induce hearing loss. The two classes I will focus on in this review two classes are aminoglycosides antibiotics and platinum-based chemotherapy therapeutics. Platinum-based therapeutics like carboplatin, oxaliplatin, and cisplatin are typically used as an antitumor agents (Kros & Steyger, 2019). Cisplatin is commonly used for treatment of bladder, cervical, ovarian, testicle, and gastrointestinal cancers.

Aminoglycosides like gentamicin, tobramycin, and kanamycin are usually are broad spectrum of antibiotics that are used for treating suspected or confirmed bacterial infections (Kros & Steyger, 2019). Additionally, they are used for long-term management of recurrent infections like cystic fibrosis or tuberculosis. In this review I will discuss aminoglycoside and cisplatin induced ototoxicity.

Ototoxic uptake by hair cells

For drugs to become ototoxins they must enter the inner ear to cause damage. To do this, these drugs must cross the blood labyrinth barrier. This barrier prevents blood cells and macromolecules to enter the cochlea (Kros & Steyger, 2019). In the cochlea there are two types of fluid in the inner ear perilymph and endolymph. Both cisplatin and aminoglycosides enter the endolymph (Li & Steyger, 2011) Once aminoglycosides enters the endolymph they enter hair cells through mechanoelectrical transduction (MET) channels, located near the tip of the stereocilia. MET channels detect mechanical stimuli created by sound pressure fluctuations (Kros & Steyger, 2019). MET channels are cation channels that have a low conductance for Ca²⁺. Aminoglycosides bind to channel pores which blocks MET channels. MET channel pores are large enough for aminoglycosides to enter the hair cells cytosol (Kros & Steyger, 2019). How specifically cisplatin enters hair cells is not totally known. Cisplatin can have multiple potential entry routes to hair cells. Cisplatin can enter hair cells through transporters. There are two potential transporters that cisplatin can be using which is copper transporter CTR1 and organic cation transporter OCT2. Additionally, cisplatin can enter hair cells through passive diffusion. Once aminoglycosides and cisplatin enter hair cells, they have been shown to cause hair cell damage and death.

Aminoglycoside-induced ototoxicity

Once aminoglycosides enter hair cells, they activate several cell death pathways by a mix of apoptosis and necrosis and likely other pathways. Apoptosis is usually defined by having caspase activation and nuclear condensation (Morrill & He, 2017). Necrosis is usually defined with having plasma and nuclear membrane swelling. Cell death pathways activate either by apoptosis or necrosis which is an accumulation of reactive oxygen species (ROS) (Morrill & He, 2017).

A major player in aminoglycoside-induced hair cell loss is the generation of reactive oxygen species (ROS). ROS are byproducts of normal metabolism oxygen do play an important role in cell signaling but an excessive amount can lead to damage. Aminoglycosides disrupt mitochondrial integrity which causes ROS which leads to hair cell death (Esterberg et al., 2016). It has been shown an increase of oxidation of both the cytoplasm and mitochondria of dying hair cells when exposed to aminoglycosides (Esterberg et al., 2016). The reason suggested that drives ROS generation when aminoglycosides are introduced is mitochondrial calcium. However, the accumulation of ROS is early start aminoglycoside induced hair cell damage (Choung et al., 2009).

A cell death pathway that is activated by aminoglycosides by the accumulation of ROS is the c-Jun pathway (JNK) (Rybak & Ramkumar, 2007). The JNK pathway is associated with regeneration, neuronal plasticity, and cell death. The pathway when activated, can translocate to the nucleus and activate genes in the cell death pathway (Rybak & Ramkumar, 2007). Then, these genes translocate to the mitochondria which causes the release of cytochrome C which triggers apoptosis by caspase-9 and -3(Rybak & Ramkumar, 2007).

One study, using chickens, researchers found that aminoglycosides activate the mitochondrial pathway that is driven by caspase-9 and -3 (Cheng et al., 2003; Rybak & Ramkumar, 2007).  During apoptosis caspases they function as primary effectors that dismantle cellular structures like DNA repair enzymes (Brentnall et al., 2013). Their main function is to control cell death and inflammation. Another study said that aminoglycosides induce alterations in calcium mobilization. Intracellular Ca²⁺ is important as it is the key regulator of deciding the survival of sensory cells like hair cells. Increasing Intracellular Ca²⁺ makes hair cells more sensitive to hair cell death (Esterberg et al., 2013). While these are only a few examples on how aminoglycosides impact cell death pathways, in the end it all leads to hair cell death. Another drug that impacts cell death pathways is cisplatin. Cisplatin and aminoglycosides have some similarities by activating the JNK pathway.

Cisplatin-Induced Ototoxicity

The exact molecular mechanism of cisplatin induced ototoxicity is not yet fully known (Callejo et al., 2015). However, one major factor is the generation of reactive oxygen species (ROS) as it promotes lipid peroxidation which causes damage to the cochlea.  

 A mechanisms that could contribute to apoptosis is p53 and caspase. When cisplatin is administered it inhibits the activity of some antioxidant enzymes and stimulates others (Callejo et al., 2015). Cisplatin stimulates NADPH oxidase 3 (NOX3), a isoform of NADPH. When activating NOX3, it has been shown to induce transient receptor potential vabilloid 1 (TRPV1) an inflammatory signaling pathway (Mukherjea et al., 2008). TRPV1 is a catatonic channel that helps mediate inflammatory pain. Cisplatin induces TRPV1 by oxidative stress and increasing ROS generation through NOX3 (Mukherjea et al., 2008; Ramkumar et al., 2021). This increase of TRPV1 activity then increases calcium ion influx in cochlear tissues expressing this ion channel which leads to cell death (Mukherjea et al., 2008). The increase in ROS generation by cisplatin is due to the depletion of glutathione and activation of NADPH oxidase (Mukherjea et al., 2008).

ROS generation and oxidative stress by NOX-3 can then activate JNK. These molecules then can translocate the nucleus in order to activate genes that play a part in cell death pathways (Rybak & Ramkumar, 2007). These genes translocate to the mitochondria and cause the release of cytochrome C which then triggers apoptosis.

ROS generation can also activate different cell death pathways by forming hydroxyl free radicals that can interact with polyunsaturated fatty acids in the cell membrane liquid bilayer can generate aldehyde 4-hydroxynonenal (4-HNE), a maker of lipid peroxidation (J. E. Lee et al., 2004).  This causes an influx of calcium into the cell which leads to apoptosis (J. E. Lee et al., 2004). Another way ROS can develop into ototoxicity is by triggering systolic migration of Bax which leads to cytochrome C to activate caspase-3 (Youn et al., 2017). The activation of caspase-3 results in apoptosis and degradation of DNA (Youn et al., 2017).  In order to prevent ROS accumulation, antioxidants can help provide protection of the early stages of apoptosis by blocking the downstream cascades of cell death (Rybak et al., 2007).

Possible Protection

The ingestion of aminoglycosides and cisplatin sometimes cannot be prevented so when taking these drugs, it is important to consider some otoprotective treatments. As previously stated, antioxidants like sodium thiosulfate can help provide upstream protection of the cochlea. They help by forming neutralized cisplatin to reduce ototoxtic activity (Rybak et al., 2007). It has been shown sodium thiosulfate helps reduce hair cell loss with reducing antitumor activity in guinea pigs when administering cisplatin (Muldoon et al., 2000; Rybak et al., 2007).

There are a few new possibilities that have potential otoprotective therapeutics. Currently in clinical trials, there is a vaccine called GV1001, an antitumor agent, which could help rescue aminoglycoside induced hearing damage (Kim et al., 2018; S.-Y. Lee et al., 2020). This vaccine is a cell-penetrating peptide that has been a used against several types of cancers like melanoma and advanced pancreatic cancer (Kim et al., 2018).  GV1001 had been shown to have antioxidant and anti-inflammatory effects. The vaccine reduces levels of oxidative stress and ROS, (S.-Y. Lee et al., 2020). Studies of the vaccine showed that hair cell death, oxidative stress and inflammatory reactions were prevented when this vaccine was delivered (Kim et al., 2018). This vaccine protected against cochlear hair cell damage in rats and has great potential for humans.

Another possible otoprotective option is stem cells. Using mesenchymal stem cells (MSCs) to help repair cochlear damage seems to have to potential in the future (Tsai et al., 2022). Researcher used MSCs as they can secrete growth factors and anti-inflammatory molecules for tissue repair and reconstruction.  In one study they used MSCs to prevent cisplatin induced ototoxicity. They found that the use of MSCs reduced hair cell damage (Tsai et al., 2022).  They found that using MSCs helped reduce the loss of hair cells, caspase-3 positive cells and overall programmed cell death all induced by cisplatin (Tsai et al., 2022).  These stem cells have the potential to help downregulate the expression of cochlear genes that are associated with apoptosis or oxidative stress (Tsai et al., 2022). While this prevention is still preliminary, it has promising potential for use for humans to prevent hearing loss once more testing is done.

Conclusion

Drug-induced hearing loss is a real problem. Many people take platinum-based therapeutics and aminoglycosides. For a lot of people abstaining from these drugs is not an option.  In this review I only talked about a few ways aminoglycosides and cisplatin induce ototoxicity but there is no disputing the fact that these drugs do cause hearing loss. The work of finding out what drugs are ototoxic is essential. In humans, hair cell damage does not get repaired. Once hearing is lost it does not come back. Finding out the specific mechanisms for which aminoglycosides and platinum-based therapeutics damage our hearing is essential for helping find otoprotective therapeutics to help.

[+] References

[+] Other Work By Olivia Molano