2025 Volume 50 Issue 6 Pages 245-261
Ototoxicity, or hearing loss and damage to the auditory system caused by certain medications, is a significant clinical challenge. Many commonly used drugs, including antimicrobials, cancer therapies, and loop diuretics, have the potential to induce temporary or permanent ototoxicity. The underlying mechanisms are complex, involving both genetic and environmental factors. Pharmacogenomics, the study of how an individual’s genetic makeup influences their response to drugs, has emerged as a promising field for understanding and mitigating ototoxicity. Developing personalized approaches to prevent and manage ototoxicity is crucial, and this is where the pharmacogenomic basis of ototoxicity becomes crucial. This review aims to provide healthcare professionals with an updated perspective on the genetics of ototoxicity by summarizing the latest research and insights in this rapidly evolving field. It presents a comprehensive overview of the mechanisms and genetic factors associated with drug-induced ototoxicity, with a particular focus on cisplatin and aminoglycoside antibiotics.
The term “ototoxicity” refers to the harmful effects that certain drugs or environmental/occupational exposures can have on the structures and functions of the inner ear. This ototoxicity can be caused by multiple factors, potentially harming the sensory hair cells or non-sensory cells that play crucial roles in maintaining the inner ear’s homeostasis, such as the cells found in the stria vascularis. These disruptions can directly impact the function of the hair cells (Tan and Song, 2023). Pharmaceutical-induced auditory impairment is a substantial clinical concern. A wide range of commonly prescribed medications, such as antimicrobial agents, cancer treatment drugs, and loop diuretics, possess the capacity to elicit temporary or irreversible damage to the hearing apparatus and the auditory system as a whole. This adverse effect, known as ototoxicity, presents a significant challenge for healthcare professionals in managing patient care and treatment plans (Rybak, 2007; Schacht et al., 2012). Certain classes of antimicrobial drugs, most notably aminoglycoside antibiotics, stand out as prime culprits in the realm of medication-induced auditory impairment. Alarmingly, the incidence of ototoxicity associated with the use of these antimicrobial agents can reach up to one-third of the patient population in some clinical settings (Selimoglu, 2007; Xie et al., 2011). Antimicrobial agents belonging to the aminoglycoside class, such as gentamicin, tobramycin, and amikacin, are extensively utilized in clinical practice to combat severe bacterial infections, particularly in hospital environments. This widespread application of aminoglycoside antibiotics is partly driven by their potent antimicrobial properties and effectiveness against a broad spectrum of pathogenic bacteria (Xie et al., 2011). Despite their therapeutic utility, a significant limitation of aminoglycoside antimicrobials is their inherent propensity to induce both temporary and permanent hearing impairment. Similarly, certain cancer chemotherapeutic agents, such as cisplatin and carboplatin, are well-documented for their ototoxic properties, which can lead to irreversible high-frequency hearing loss in patients undergoing these cancer treatments (Rybak, 2007; Coradini et al., 2007). In addition to antimicrobials and cancer therapies, loop diuretics, which are commonly prescribed for the management of conditions such as heart failure and hypertension, have also been linked to transient as well as permanent ototoxicity in some clinical scenarios (Rybak and Ramkumar, 2007; Rybak, 1993).
The underlying mechanisms driving ototoxicity are multifaceted, with both genetic and environmental factors playing crucial roles (Steyger, 2021b; Rybak et al., 2019). The genetic landscape also plays a significant part in an individual’s predisposition to ototoxicity. Certain inherent genetic mutations and variants can confer an increased susceptibility to adverse auditory effects from medications. As a prime example, specific mutations within the mitochondrial DNA (mtDNA) have been closely linked to a heightened vulnerability to aminoglycoside-induced hearing impairment (Foster II and Tekin, 2016; Nguyen and Jeyakumar, 2019). Genetic variations can disrupt the normal functioning of mitochondria, the cellular organelles responsible for energy production. This mitochondrial impairment increases the susceptibility of the delicate sensory hair cells within the inner ear to the oxidative stress and programmed cell death (apoptosis) induced by ototoxic pharmaceutical agents (Huth et al., 2011). Aside from genetic predispositions, an individual’s susceptibility to ototoxicity can also be influenced by various environmental and clinical factors. Characteristics such as advanced age, pre-existing hearing difficulties, and concurrent administration of other potentially ototoxic drugs, including loop diuretics and cisplatin, can work together to exacerbate the damaging impact on the auditory system (Frisina et al., 2016; Barbieri et al., 2019). Moreover, underlying medical conditions, such as renal impairment, can also play a role in ototoxicity by compromising the clearance and pharmacokinetics of these potentially ototoxic drugs. This can result in higher local concentrations within the inner ear, further intensifying the ototoxic damage (Mamillapalli et al., 2020; Forge, 2018).
The study of how an individual’s genetic makeup influences their response to drugs, has emerged as a promising field for understanding and mitigating ototoxicity (Lee, 2014; Ghafari, 2023). The intricate relationship between an individual’s genetic makeup and their environmental exposures highlights the importance of a tailored approach to addressing and managing ototoxicity. Ongoing research efforts are focused on advancements in the field of pharmacogenomics, the development of protective interventions for the auditory system, and the optimization of dosing protocols for ototoxic pharmaceuticals - all with the aim of overcoming this significant clinical challenge through personalized strategies (Pasdelou et al., 2024; Cannizzaro et al., 2014). This review aims to provide an up-to-date summary of the current understanding surrounding the genetics of ototoxicity. It presents a comprehensive overview of the underlying mechanisms and genetic factors associated with drug-induced ototoxicity, with a particular emphasis on cisplatin and aminoglycoside-induced hearing loss. Additionally, the review explores the pharmacogenetics and clinical genetic testing of ototoxicity, while also discussing the ongoing challenges and future research directions in this field. This review specifically seeks to address the question: “What are the key genetic genes and variants contributing to ototoxicity, particularly in relation to aminoglycosides and cisplatin?” By exploring this question, we seek to highlight the importance of personalized approaches in managing ototoxicity.
The degree of susceptibility to hearing impairment among patients undergoing treatment with cisplatin or aminoglycosides can vary considerably, leading to extensive research efforts aimed at identifying the risk factors that influence an individual’s vulnerability to the ototoxic effects of these drugs. While some medications may carry a relatively low risk of ototoxic side effects, prescribing physicians should remain aware of these potential adverse outcomes and carefully weigh the benefits against the risks for each patient.
The journey of sound begins as the waves travel through the external auditory canal, eventually reaching the eardrum and progressing through the ossicular chain. This movement of the stapes within the perilymph generates fluid waves that propagate towards the basilar membrane, where the inner and outer hair cells (IHCs and OHCs) are arranged in an organized manner. These fluid waves induce displacement of the basilar membrane, which in turn leads to the deflection and depolarization of the hair cells’ stereocilia. Notably, the OHCs possess a unique characteristic – they can contract in response to depolarization. The OHCs located in the apical region of the cochlea amplify low-frequency sounds, while those in the basal region amplify high-frequency sounds. This amplification is achieved through the coordinated movement of the basilar membrane, which the rows of OHCs facilitate. This coordinated movement of the basilar membrane leads to the depolarization of the IHC row. The depolarization of the IHCs then triggers the release of neurotransmitters at the ribbon synapses in the spiral ganglion neurons (SGNs) and the cochlear nerve, ultimately generating an action potential that conveys the auditory information to the central nervous system (Reynard and Thai-Van, 2024). The issue of ototoxicity is primarily understood as a phenomenon centered within the inner ear; however, it is crucial to recognize that ototoxic agents can also exert their effects on the ribbon synapses and SGNs. Moreover, the concept of cochlear amplification is intrinsically tied to the electro-motile properties of the OHCs, which are enabled by the lateral membrane proteins called prestin. These active contraction movements of the OHCs necessitate a reliable energy supply, which is furnished by the nearby mitochondria. Notably, recent literature has placed substantial emphasis on investigating the role of mitochondrial dysfunction and oxidative stress in the development of sensorineural hearing loss (SNHL) (Tan and Song, 2023; Wang and Puel, 2018). Mitochondrial dysfunction can have various underlying causes, such as inherited mtDNA mutations, age-related acquired mutations, excessive mitochondrial workload, disruptions in calcium regulation, or the accumulation of ototoxic drugs. In a recent review, Ibrahim et al. (2018) examined 20 specific mtDNA mutations, affecting either ribosomal RNA (rRNA) or transfer RNA (tRNA), that have been linked to the development of SNHL as reported in the scientific literature (Ibrahim et al., 2018).
Mitochondria are increasingly recognized as pivotal regulators of cellular processes, particularly in terms of cell survival and death. These organelles are the primary intracellular source of reactive oxygen species (ROS), which include both free radical species such as superoxide anion and hydroxyl radical, as well as non-radical forms like hydrogen peroxide (Tan and Song, 2023; Wang and Puel, 2018). ROS are tightly regulated by endogenous antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione (Someya and Kim, 2021). However, an imbalance between ROS production and the level of antioxidant defense within the cell leads to a state of oxidative stress. This oxidative stress is associated with irreversible cellular damage, ultimately resulting in hair cell death and the development of hearing loss (Wang and Puel, 2018; Böttger and Schacht, 2013). Given the high metabolic requirements of sensory hair cells, the stria vascularis, and SGNs, these structures are particularly vulnerable to the detrimental effects of ROS. The cochlea functions as a largely self-contained system, with limited capacity to expel accumulated toxins at the same rate. Consequently, an imbalance occurs, leading to an overabundance of ROS coupled with a deficient antioxidant defense system. This scenario triggers increased lipid peroxidation, initiating a cascade of apoptosis (programmed cell death) in the hair cells, supporting cells, stria vascularis cells, and even the SGNs (Rabiço-Costa et al., 2020). Ototoxicity is typically considered a permanent condition. However, some animal studies and isolated human cases suggest a potential mechanism of reversibility. This proposed mechanism suggests that initial damage to the marginal cells of the stria vascularis, such as that caused by exposure to cisplatin, may be recoverable if the body’s reparative processes are allowed to occur uninterrupted. Conversely, if the accumulation of the toxic medication continues, the chances of recovery are exhausted, leading to permanent destruction of the outer hair cells and the resulting permanent hearing loss (Truong et al., 2007). Understanding the mechanisms behind ototoxicity, as well as identifying common and individual risk factors, allows for the development of strategies aimed at preventing these debilitating long-term side effects.
Cisplatin is associated with a variety of adverse side effects, including nausea, vomiting, neurotoxicity, nephrotoxicity, and ototoxicity. The neurotoxic, nephrotoxic, and ototoxic properties of cisplatin often limit the dosage that can be safely administered. Cisplatin-induced SNHL is a particularly concerning side effect, as it typically manifests within days to weeks after treatment and is often bilateral in nature (Brock et al., 2012). The initial impact of cisplatin-induced hearing loss is typically observed in the high-frequency range. However, if treatment is continued, the hearing impairment can progress to affect lower frequencies as well, ultimately leading to more severe and widespread hearing loss. Interestingly, in some cases, the hearing deterioration can even continue to worsen after the cessation of cisplatin treatment. Conversely, there have been rare reports of hearing improvement observed in a few individuals after the completion of therapy (Weissenstein et al., 2012; Truong et al., 2007). Tinnitus, or the perception of ringing or buzzing sounds in the ears, has been identified as a common side effect of cisplatin treatment, with an incidence rate ranging from 25 to 50% of cases. In a significant proportion of these cases, the tinnitus persists for at least one year after the completion of cisplatin therapy (Vermorken et al., 1983). In addition to hearing impairment, other otic symptoms associated with cisplatin administration include vertigo, with or without accompanying nausea (Vermorken et al., 1983). The extensive clinical experience with the use of cisplatin has allowed researchers to identify various risk factors associated with cisplatin-induced ototoxicity. The degree of ototoxicity is directly influenced by the dose, route, and duration of cisplatin administration. Specifically, bolus infusions of cisplatin have been shown to be more ototoxic compared to short-term or continuous infusion methods (Vermorken et al., 1983). The available evidence suggests that there is currently no clear indication that continuous infusions of cisplatin are less ototoxic compared to shorter infusion durations (Vermorken et al., 1983). Instead, the risk of cisplatin-induced ototoxicity appears to be primarily associated with the magnitude of the individual single dose as well as the overall cumulative dose administered to the patient over the course of treatment (Vermorken et al., 1983). Aside from the dosage-related factors, various patient-specific characteristics have also been identified as risk factors for cisplatin-induced ototoxicity. These include young patient age (≤4 years), concurrent cranial radiation therapy, exposure to noise, co-administration of other ototoxic or nephrotoxic drugs (such as loop diuretics or aminoglycosides), additional treatment with carboplatin, as well as pre-existing hearing impairment or renal insufficiency. The reported incidence rates for cisplatin-induced ototoxicity can vary considerably, ranging from 13% to 95%, depending on the specific ototoxicity assessment methods used and the distribution of these risk factors within the studied patient population (Langer et al., 2013). The precise mechanism underlying cisplatin-induced ototoxicity appears to involve damage to the hair cells within the cochlea. Based on extensive research using animal models, the initial impact is observed in the outer hair cells located in the basal region of the cochlea, which aligns with the characteristic high-frequency hearing impairment seen in patients. However, with continued cisplatin exposure, the damage progresses to affect the outer hair cells in the medial and apical portions of the cochlea, as well as the inner hair cells. This results in the eventual involvement of lower frequencies, including those essential for speech perception. Animal studies have further revealed that the degeneration of the hair cells is accompanied by a breakdown in the function of the blood-labyrinth barrier and a reduction in the endolymphatic potential within the inner ear (Laurell et al., 2000).
The precise molecular pathways that underlie the degeneration of cochlear structures in response to cisplatin treatment are not yet fully elucidated. However, studies in mouse models have identified the presence of two key cisplatin uptake transporters, copper transporter 1 (CTR1) and organic cation transporter 2 (OCT2), within the cochlea. CTR1 and OCT2 contribute to cisplatin uptake and are the key mediators of cisplatin entry into OHCs. This suggests that the accumulation of cisplatin within the cochlear tissues may play a central role in mediating the ototoxic effects observed with this chemotherapeutic agent (Ciarimboli et al., 2010). The available evidence indicates that the OCT2 cisplatin uptake transporter is expressed in both the hair cells and the marginal cells of the stria vascularis within the cochlea (Ciarimboli et al., 2010) . Interestingly, a more pronounced expression of OCT2 has been observed in the basal region of the cochlea, which could help explain the characteristic initial high-frequency hearing impairment associated with cisplatin ototoxicity. Furthermore, studies conducted by Thomas and colleagues in guinea pigs have demonstrated the presence of platin-DNA adducts, formed by cisplatin or carboplatin exposure, within the hair cells of the cochlea as well as the marginal cells of the stria vascularis. This suggests that the accumulation of these platinum-based chemotherapeutic agents in these critical cochlear structures may be a significant factor in the development of ototoxicity (Thomas et al., 2006). Given the non-proliferative nature of the cochlear hair cells and marginal cells, alternative mechanisms have been proposed to account for the observed cochlear damage. One potential explanation suggests that cisplatin exposure may lead to an increase in the generation of ROS within the mitochondria of these cells. This excessive oxidative stress could then result in the decompensation or impairment of the normal oxidative metabolic processes in these critical cochlear structures (Rybak et al., 2007). The unique characteristics of mtDNA may contribute to its susceptibility to cisplatin-induced damage. Unlike nuclear DNA, mtDNA lacks the protective histone proteins, making it more vulnerable to the binding and adduct formation by cisplatin molecules, as demonstrated in preclinical studies using tumor cell lines. The lack of histones on mtDNA appears to facilitate the direct interaction and binding of cisplatin, leading to the formation of platinum-DNA adducts. This increased susceptibility of mtDNA to cisplatin-mediated damage has been observed in various in vitro and preclinical models utilizing different types of tumor cells. The heightened sensitivity of mtDNA to cisplatin, compared to the nuclear DNA, may have important implications for understanding the mechanisms underlying the ototoxic effects of this chemotherapeutic agent. The accumulation of cisplatin-induced damage to mitochondrial genetic material could potentially disrupt the normal functioning of these organelles, leading to increased oxidative stress and metabolic decompensation in the affected cell populations, such as the cochlear hair cells and marginal cells (Yang et al., 2006). The persistent nature of cisplatin-induced damage to mtDNA further compounds the vulnerability of these organelles to the detrimental effects of the chemotherapeutic agent. Studies have shown that the platinated nucleotides, or cisplatin-DNA adducts, are eliminated from mtDNA at a slower rate compared to the nuclear DNA (Olivero et al., 1997). This prolonged retention of the platinum-based modifications on the mitochondrial genetic material suggests that mtDNA is more susceptible to sustained DNA damage. The persistence of these cisplatin-induced lesions on mtDNA has important implications. It is hypothesized that the impairment of transcription and translation of mitochondrial proteins, due to the platination of the mtDNA, can significantly disrupt the normal functioning of these critical organelles (Yang et al., 2006). Additionally, the direct platination of mitochondrial proteins may further compromise their structural integrity and biological activities. Together, these mechanisms – the sustained DNA damage and the impairment of mitochondrial protein function – are believed to negatively impact the overall energy metabolism within these organelles. This metabolic decompensation is then postulated to lead to an increased generation of ROS, further exacerbating the oxidative stress experienced by the affected cells, such as the cochlear hair cells and marginal cells.
Although aminoglycosides are highly effective and relatively inexpensive, they are known to have ototoxicity, nephrotoxicity, neuromuscular blockade and vestibular toxicity (Le et al., 2023; Rosenberg et al., 2020). The precise mechanisms driving aminoglycoside-induced ototoxicity remain complex and not yet fully understood. However, several critical pathways have been identified through research. One prominent hypothesis suggests that aminoglycoside antibiotics have a propensity to selectively accumulate within the sensory hair cells of the inner ear. This targeted accumulation appears to then trigger the generation of ROS and induce oxidative stress within these specialized cells. The excessive oxidative damage resulting from this process is believed to be a key factor in ultimately leading to the apoptosis and necrosis of the hair cells. This progressive loss of the critical hair cell population in the inner ear is ultimately responsible for the hearing impairment observed with aminoglycoside therapy (Selimoglu, 2007; Huth et al., 2011). In addition to the deleterious effects on the sensory hair cells, aminoglycoside antibiotics have also been observed to potentially disrupt the normal function of the stria vascularis. The stria vascularis plays a vital role in maintaining the precise ionic composition of the endolymph, the fluid-filled compartment that is essential for the proper functioning of the auditory system. Disruption of the stria vascularis by aminoglycosides may lead to the imbalance or decompensation of this delicate ionic homeostasis (Pressé et al., 2023). Based on investigations using animal models, it has been observed that aminoglycoside antibiotics can have a detrimental impact on the hair cells located within the cochlea. Initially, the outer hair cells situated in the basal region of the cochlea are affected, which leads to impairment in the individual’s ability to perceive high-frequency sounds. With continued exposure to these medications, the damage progresses towards the upper turns of the cochlea, as well as the inner hair cells, ultimately resulting in hearing impairment at speech frequencies or even complete deafness. Furthermore, aminoglycosides have also been shown to cause harm to the stria vascularis, the marginal cells, and the spiral ganglion, which are all crucial components of the auditory system (Xie et al., 2011). Interestingly, animal studies have not detected any significant accumulation of aminoglycosides in the peri- and endolymph within the inner ear. In these fluid-filled compartments, the concentration of aminoglycosides was found to be only approximately one-tenth of the concentration observed in the individual’s serum. This suggests that the mechanism by which aminoglycosides exert their damaging effects on the auditory system may not be directly related to the direct exposure of the inner ear structures to high concentrations of these antibiotics (Tran Ba Huy et al., 1986). The observation that aminoglycoside concentrations in the inner ear fluids are significantly lower than those in the serum suggests that these antibiotics may gain access to the inner ear through active transport mechanisms, rather than passive diffusion. Researchers have identified several potential transporter candidates that may facilitate the entry of aminoglycosides into the inner ear, including the endocytosis receptors LRP2 (also known as megalin) and cubulin, the transient receptor potential (TRP) cation channel, and the mechanoelectrical transducer (MET) channels. These specialized transport systems may play a crucial role in the delivery of aminoglycosides to the delicate structures within the cochlea, ultimately leading to the observed hair cell damage and hearing impairment (Nagai and Takano, 2014). In a comprehensive review, Steyger (Steyger, 2021a) explored the mechanisms of aminoglycoside uptake and transport within the inner ear. The findings suggest that these antibiotics are cleared slowly from the inner ear fluids, with elimination half-lives ranging from 10 to 13 days following a single dose. However, when multiple doses are administered, the elimination half-life can increase dramatically, reaching up to 30 days (Xu et al., 2024). This prolonged retention of aminoglycosides within the inner ear compartments may contribute to the sustained and progressive damage observed in the hair cells and other sensitive structures. The precise mechanism by which these antibiotics induce damage to the inner ear structures remains not fully understood. However, substantial evidence suggests that oxidative stress plays a key role, triggering apoptosis and necrosis in the hair cells of the cochlea, as well as in the marginal cells and the stria vascularis. It is believed that aminoglycosides interfere with bacterial ribosomes and inhibit protein biosynthesis in these microorganisms. Interestingly, the mitochondrial ribosomes in eukaryotic cells are structurally more similar to the bacterial ribosomes than the ribosomes found in the cytosol, which may contribute to the ototoxic effects observed in the inner ear (Tan and Song, 2023).
By inhibiting mitochondrial protein biosynthesis, these antibiotics impair the function of the enzyme aconitase, which is crucial for cellular respiration. This, in turn, leads to an accumulation of ferric cations within the cells. Aminoglycosides are able to complex with these cations and subsequently trigger the Fenton reaction, resulting in the generation of ROS (Hsieh et al., 2024). Furthermore, the Fe2+/3+-Aminoglycoside-complex can form a ternary complex with arachidonic acid, further promoting ROS formation through lipid peroxidation (Ungur et al., 2022). Given the high prevalence of mitochondria in the cells of the inner ear, these structures are considered particularly vulnerable to the ototoxic effects of aminoglycosides (Schacht et al., 2012).
The susceptibility of patients to experience hearing impairment following treatment with cisplatin or aminoglycosides can vary significantly. Considerable efforts have been made to identify the risk factors that determine an individual’s predisposition to the ototoxic effects of these drugs. Understanding the specific factors that contribute to an individual’s vulnerability to drug-induced hearing loss is crucial for developing personalized treatment strategies and mitigating the risk of this debilitating side effect (Steyger, 2021a). One of the key factors contributing to the variability in an individual’s susceptibility to ototoxicity is the role of genetic determinants. Extensive research has been conducted to investigate the potential association between specific genetic variants and an increased risk of developing cisplatin- or aminoglycoside-induced hearing impairment. By identifying the genetic markers that confer a heightened vulnerability to drug-related ototoxicity, researchers aim to better understand the underlying mechanisms and develop more personalized approaches to mitigate this adverse effect (Pussegoda, 2012; Rivetti et al., 2023; Cacabelos et al., 2021). Researchers have employed both targeted candidate gene studies and high-throughput screening approaches to identify a range of genetic variants that may be associated with an individual’s predisposition to drug-induced ototoxicity. These genetic markers, once discovered, have the potential to serve as predictive tools, allowing clinicians to assess a patient’s risk profile and guide treatment decisions accordingly.
The candidate gene approach has primarily focused on investigating genes that are believed to play a central role in the detoxification and transport of cisplatin. These include genes encoding glutathione-S-transferases (GSTs), which are involved in the metabolism and clearance of cisplatin, as well as genes encoding enzymes involved in DNA repair pathways. Researchers have also explored genes encoding proteins like OCT2 and CTR1, which are responsible for the cellular uptake and transport of cisplatin, as potential contributors to an individual’s susceptibility to cisplatin-induced ototoxicity (Quintanilha et al., 2019). Studies focusing on the candidate gene approach have reported potential protective effects against cisplatin-induced ototoxicity in certain genetic variants. For instance, the deletion of a GSTT1 allele and/or the presence of the GSTP1 SNP rs1695 have been associated with a reduced risk of cisplatin-induced hearing loss in adults with testicular cancer. These findings suggest that genetic differences in the genes encoding glutathione-S-transferases may play a role in modulating an individual’’s susceptibility to the ototoxic effects of cisplatin (Lui et al., 2018; Macedo et al., 2023). GSTM3 SNP rs1799735 has been associated with a reduced risk of cisplatin-induced ototoxicity among children undergoing cancer treatment. This suggests that genetic differences in the GSTM3 gene, which encodes another member of the glutathione-S-transferase family, may confer a degree of protection against the ototoxic effects of cisplatin in the pediatric cancer population. (Lui et al., 2018). In addition to the genetic variants related to glutathione-S-transferases, studies have also identified other genetic markers associated with altered susceptibility to cisplatin-induced ototoxicity. Specifically, the presence of the SNP rs316019 in the OCT2 gene has been linked to a protective effect, both in children and adults undergoing cisplatin treatment. Conversely, the LRP2 SNP rs2075252 and XPC SNP rs228001, which are linked to cellular transport and DNA repair functions respectively, have been associated with an increased risk of cisplatin-induced hearing loss. These findings suggest that genetic variations in genes involved in the transport, detoxification, and DNA repair pathways may all contribute to an individual’s predisposition to this adverse effect of cisplatin (Lanvers-Kaminsky et al., 2015; Tserga et al., 2019). The first high-throughput screen, which analyzed variations in drug metabolizing genes attracted considerable attention. One such high-throughput study focused on analyzing genetic variations in drug-metabolizing genes and identified two specific single nucleotide polymorphisms (SNPs) associated with an increased risk of cisplatin-induced hearing loss in children with various types of cancer. The study found that the presence of the SNP rs12201199 in the thiopurine-S-methyltransferase (TPMT) gene and/or the SNP rs93323377 in the catechol-O-methyltransferase (COMT) gene were linked to a heightened susceptibility to this adverse effect of cisplatin in the pediatric population (Talach et al., 2016). Expanding beyond candidate gene studies, researchers have also conducted genome-wide association studies (GWAS) to explore the potential genetic underpinnings of cisplatin-induced ototoxicity. One such GWAS study has identified a significant association between a specific SNP, rs1872328, located within the acylphosphatase 2 (ACYP2) gene, and an increased risk of cisplatin-induced hearing loss in patients with medulloblastoma. This finding suggests that genetic variations in the ACYP2 gene, which is involved in cellular processes such as metabolism and signaling, may play a role in modulating an individual’s susceptibility to the ototoxic effects of cisplatin, highlighting the value of unbiased, genome-wide approaches in uncovering novel genetic markers. (Clemens et al., 2020). In addition, the association between cisplatin ototoxicity and the TPMT SNP rs12201199 and the COMT SNP rs93323377 was confirmed in a separate cohort of cancer patients (Thiesen et al., 2017; Ross et al., 2009a; Pussegoda et al., 2013), However, the previously reported protective effects of the GSTM1 deletion, the GSTP1 SNP rs1695, and the GSTM3 SNP rs1799735 have not been corroborated by other research groups. This highlights the need for further large-scale, well-designed investigations to better elucidate the complex genetic landscape underlying an individual’s susceptibility to this adverse effect of cisplatin treatment. (Langer et al., 2013). The failure to replicate research findings does not necessarily mean the observed association is false. The biological mechanisms underlying the effects of the chemotherapy drug cisplatin are multifaceted, involving the interplay of numerous genes that mediate its actions, resistance, and detoxification. Cancer treatment often employs a combination of different anticancer drugs, each of which may utilize similar detoxification pathways and resistance mechanisms as cisplatin. The specific combination of drugs used in different treatment protocols can impact the degree to which various detoxification and resistance pathways are affected. Consequently, genetic variations in the genes involved in these processes may have varying effects on the risk of cisplatin-induced ototoxicity depending on the treatment regimen. Additionally, factors such as the grading of ototoxicity and the distribution of other risk factors, like age or the use of other ototoxic medications, can also influence the significance of genetic variants in predicting cisplatin-induced hearing impairment.
Mitochondria possess their own distinct genetic material with a specialized genetic code. In mammals, the mitochondrial genome is passed down exclusively through the maternal lineage. This inheritance pattern has been observed in cases where susceptibility to certain aminoglycoside antibiotics is transmitted maternally within families. The two most extensively studied mutations associated with this maternally inherited trait are the m.1555A>G and m.1494C>T substitutions, both of which occur within the 12S rRNA gene that is part of the 39S subunit of the mitochondrial ribosome (Rivetti et al., 2023; Gao et al., 2017). Rivetti et al. (Rivetti et al., 2023) reviewed the molecular underpinnings of ototoxicity-induced hearing impairment, drawing insights from the mitochondrial genome analyses of several family pedigrees, including three Chinese families and a large Arab-Israeli lineage. They highlighted the association of the m.1555A>G mutation within the 12S rRNA gene with maternally inherited, non-syndromic hearing loss, noting that this mutation was absent in the 278 control subjects examined in the studies they analyzed (Rivetti et al., 2023). Indeed, it has been revealed that the m.1555A>G genetic variant modifies the binding interactions between aminoglycoside drugs and the A-site of ribosomal RNA, resulting in structural changes to the 12S rRNA molecule (Guan, 2011). Since this pivotal discovery, families exhibiting maternally inherited patterns of hearing loss associated with the m.1555A>G mutation have been reported across a wide range of populations, including Asian, Caucasian, and African ethnic backgrounds, as well as in numerous isolated cases (Borisova et al., 2024; Igumnova et al., 2019; Cernada et al., 2014). Another mitochondrial genome mutation at position 1494 (m.1494C>T) in a large Chinese family affected by ototoxicity-induced hearing loss has been identified (Zhao et al., 2004). Given that the m.1494 position corresponds to the highly conserved m.1555 site within the 12S rRNA gene’s A-site, it is reasonable to infer that this homoplastic mutation also contributes to heightened sensitivity to aminoglycoside antibiotics. In addition, researchers also observed that in the absence of aminoglycoside exposure, the severity of hearing impairment and the age at which it manifests can vary among affected individuals within the same matrilineal lineage. Furthermore, they found that the administration of aminoglycoside antibiotics can either induce or exacerbate hearing loss in these maternally-inherited cases. This key finding was later corroborated by additional studies conducted in Spanish and Chinese populations (Wang et al., 2006; Chen et al., 2015, Han et al., 2007, Rodríguez-Ballesteros et al., 2006).
While the m.1555A>G and m.1494C>T mutations occur at corresponding positions within the genetic code and have both been observed in hearing loss cases across diverse ethnic populations, the m.1555A>G variant appears to be more prevalent. Furthermore, the distribution of the m.1555A>G mutation in hearing impairment exhibits a distinct ethnic and geographic pattern. Focusing specifically on drug-induced deafness, the incidence of the m.1555A>G mutation was found to be approximately 33% within two Japanese ethnic groups examined (Usami et al., 2000; Noguchi et al., 2004), 13%, 12.29%, 10.4%, and 5% in four Chinese ethnic populations (Li and Steyger, 2011; Li et al., 2014; Li et al., 2004), and 17% in two white ethnic populations in the United States and Spain (Fischel-Ghodsian et al., 1993; Estivill et al., 1998). In contrast to the m.1555A>G mutation, the frequency of the m.1494C>T variant appears to be much lower. In a study of 1642 Chinese children with hearing loss, the m.1555A>G mutation was detected in 3.96% of the subjects, while the m.1494C>T mutation was present in only 0.18% of the cases. This data suggests the m.1555A>G mutation is significantly more common than the m.1494C>T alteration, at least within the Chinese population examined (Lu et al., 2010). Additionally, the m.1494C>T variant appears to be exceedingly rare. This is evidenced by a study of sporadic hearing-impaired subjects in Spain, where only 3 cases of the m.1494C>T mutation were identified among 1340 individuals examined. This stark disparity in prevalence further underscores the markedly lower frequency of the m.1494C>T alteration compared to the m.1555A>G mutation across different ethnic populations (Rodríguez-Ballesteros et al., 2006). Beyond the m.1555A>G and m.1494C>T variants, further sequence analysis of the complete mitochondrial genome has revealed several additional mtDNA mutations linked to ototoxicity-induced hearing impairment. Notably, Zhao and colleagues reported that the m.1095T>C mutation was correlated with ototoxicity and non-syndromic hearing loss in three Chinese families affected by this condition (Zhao et al., 2005). This T-to-C substitution, located within the 12S rRNA gene, was found to disrupt the highly conserved stem-loop structure of helix 25 (Neefs et al., 1991). Significantly, the m.1095T>C mutation was identified in affected individuals, but not in 364 Chinese control subjects. This alteration may potentially impact the initiation of mitochondrial protein synthesis, consequently leading to mitochondrial dysfunction, which could contribute to the ototoxicity-induced hearing loss observed in these Chinese families (Jing et al., 2015a; Thyagarajan et al., 2000). Additionally, insertions or deletions at the 961 position within the mitochondrial genome have been associated with ototoxicity-induced deafness in several unrelated family groups (Bacino et al., 1995; Casano et al., 1999; Konings et al., 2008). This specific location is situated in the C-cluster region between loops 21 and 22 of the 12S rRNA (Pham et al., 2022). However, this particular genomic area is not highly conserved evolutionarily, and its precise functional roles, especially in relation to aminoglycoside interactions in bacterial homologs, remain unclear. Furthermore, a comprehensive screening of the 12S rRNA gene sequences collected from Chinese children diagnosed with hearing impairment revealed several other mtDNA mutations that may be linked to either aminoglycoside ototoxicity or non-syndromic hearing loss. These include m.745A>G, m.792C>T, m.801A>G, m.839A>G, m.856A>G, m.1027A>G, m.1192C>T, m.1192C>A, m.1310C>T, m.1331A>G, m.A374A>G, m.1452T>C and m.1537C>T (Lu et al., 2010; Lévêque et al., 2007; Konings et al., 2008; Jing et al., 2015b) (Table 1).
| Genetic Factor | Association with Ototoxicity | Reference |
|---|---|---|
| GSTT1 deletion (nDNA) | Protection from cisplatin-induced ototoxicity in adults with testicular cancer | (Lui et al., 2018, Macedo et al., 2023) |
| GSTP1 SNP rs1695 (nDNA) | Protection from cisplatin-induced ototoxicity in adults with testicular cancer | (Lui et al., 2018, Macedo et al., 2023) |
| GSTM3 SNP rs1799735 (nDNA) | Protection from cisplatin-induced ototoxicity in children with various cancers | (Lui et al., 2018) |
| OCT2 SNP rs316019 (nDNA) | Protection from cisplatin-induced ototoxicity in children and adults | (Lanvers-Kaminsky et al., 2015) |
| LRP2 SNP rs2075252 (nDNA) | Increased risk for cisplatin-induced ototoxicity | (Tserga et al., 2019) |
| XPC SNP rs228001 (nDNA) | Increased risk for cisplatin-induced ototoxicity | (Tserga et al., 2019) |
| TPMT SNP rs12201199 (nDNA) | Increased risk for cisplatin-induced ototoxicity in children with various cancers | (Talach et al., 2016, Thiesen et al., 2017, Ross et al., 2009a, Pussegoda et al., 2013) |
| COMT SNP rs93323377 (nDNA) | Increased risk for cisplatin-induced ototoxicity in children with various cancers | (Talach et al., 2016, Thiesen et al., 2017, Ross et al., 2009a, Pussegoda et al., 2013) |
| ACYP2 SNP rs1872328 (nDNA) | Increased risk for cisplatin-induced ototoxicity in medulloblastoma patients | (Clemens et al., 2020) |
| m.1555A>G (mtDNA, 12S rRNA gene) | Increased risk for aminoglycoside-induced ototoxicity | (Rivetti et al., 2023, Gao et al., 2017) |
| m.1494C>T(mtDNA, 12S rRNA gene) | Increased risk for aminoglycoside-induced ototoxicity | (Rivetti et al., 2023, Gao et al., 2017) |
| m.792C>T(mtDNA, 12S rRNA gene) | Increased risk for aminoglycoside-induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.801A>G (mtDNA, 12S rRNA gene) | Increased risk for aminoglycoside-induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.839A>G(mtDNA, 12S rRNA gene) | Increased risk for aminoglycoside-induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.745A>G(mtDNA, 12S rRNA gene) | Increased risk for aminoglycoside-induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.856A>G (mtDNA) | Increased risk for aminoglycoside-induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.1027A>G (mtDNA) | Increased risk for aminoglycoside-induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.1192C>T (mtDNA) | Increased risk for aminoglycoside-induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.1192C>A (mtDNA) | Increased risk for aminoglycoside-induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.1310C>T (mtDNA) | Increased risk for aminoglycoside-induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.1331A>G (mtDNA) | Increased risk for aminoglycoside -induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.A374A>G (mtDNA) | Increased risk for aminoglycoside -induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.1452T>C (mtDNA) | Increased risk for aminoglycoside -induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
| m.1537C>T (mtDNA) | Increased risk for aminoglycoside -induced ototoxicity | (Li et al., 2004, Lévêque et al., 2007, Konings et al., 2008, Lu et al., 2010) |
Beyond the previously mentioned mitochondrial mutations, additional genomic alterations have been discovered that may also confer susceptibility to aminoglycoside-induced hearing loss. The BCL-2 (B-cell lymphoma 2) protein family is a well-studied group that plays a crucial role in regulating apoptosis, or programmed cell death. These family members can be broadly classified as either anti-apoptotic or pro-apoptotic. The anti-apoptotic subset primarily includes proteins like Bcl-2 and Bcl-xL, while the pro-apoptotic group encompasses Bax, Bak, Bcl-xS, Bid, Bad, Bim, and others. Specifically, in HEI-OC1 cell line experiments, cisplatin-induced apoptosis has been observed to correlate with the activation and translocation of Bid and Bax proteins, as well as the release of cytochrome-c. This suggests that dysregulation of the delicate balance between pro- and anti-apoptotic BCL-2 family members may contribute to the ototoxicity associated with certain pharmacological agents (Xie et al., 2021; Gill et al., 2024).
Genetic testing for specific genetic variants can play a crucial role in predicting an individual’s risk of developing ototoxicity, which is hearing loss or damage to the inner ear caused by certain medications or drugs. By identifying these genetic markers, healthcare providers can gain valuable insights that can guide personalized treatment strategies for their patients (Langer et al., 2020). Patients who are identified as being at a high risk of developing ototoxicity based on their genetic profile may benefit from a more proactive and targeted approach to their care. This could involve closer monitoring of their hearing function during the course of treatment, the use of otoprotective agents that can help mitigate the damaging effects of the ototoxic drugs, or the consideration of alternative treatment options that pose a lower risk of causing hearing loss (Langer et al., 2020; Dionne et al., 2012). By incorporating genetic testing into the clinical management of patients who are prescribed ototoxic drugs, healthcare providers can make more informed decisions about the most appropriate course of action for each individual. This can lead to the optimization of treatment plans, ultimately improving patient outcomes by minimizing the risk of devastating and potentially irreversible hearing loss. Understanding the underlying genetic mechanisms is essential for predicting an individual’s prognosis and guiding personalized treatment strategies.
Researchers have developed a genetic screening test that can help predict the likelihood of ototoxicity development in pediatric patients undergoing cisplatin treatment (Rajput et al., 2024; Ross et al., 2009b). The test results indicate that approximately one-third of children are expected to receive a positive outcome, and those individuals have an almost certain chance of experiencing serious ototoxicity if given standard cisplatin dosages. However, this genetic test cannot be used to definitively rule out the risk, as around half of those who test negative will still go on to develop severe ototoxicity. Interestingly, certain genetic markers have been associated with a reduced risk of cisplatin-induced ototoxicity. These protective variants include GSTT1 allele deletion, the GSTP1 SNP rs1695, the GSTM3 SNP rs1799735, and the OCT2 SNP rs316019. The presence of these genetic markers appears to confer a protective effect against cisplatin-induced hearing loss in both adult and pediatric cancer patients. Therefore, individuals carrying these beneficial genomic variants may be less susceptible to experiencing ototoxic side effects from cisplatin chemotherapy regimens.
Genetic markers associated with reduced risk of cisplatin-induced ototoxicity include GSTT1 Allele Deletion, GSTP1 SNP rs1695, GSTM3 SNP rs1799735 and OCT2 SNP rs316019. These genetic variants appear to have a protective effect against cisplatin-induced hearing loss in both adult and pediatric cancer patients. Patients carrying these genetic markers may be less susceptible to ototoxic side effects from cisplatin chemotherapy. In addition, genetic markers associated with increased risk of cisplatin-induced ototoxicity include LRP2 SNP rs2075252, TPMT SNP rs12201199, COMT SNP rs93323377 and ACYP2 SNP rs1872328. Individuals with these genetic variants may be at higher risk of experiencing cisplatin-induced hearing loss and ototoxicity. Genetic testing for these markers could help identify patients who may need closer monitoring, dose adjustments, or alternative treatment options to mitigate the risk of permanent hearing damage. While these genetic variants have been associated with an increased risk of ototoxicity, the strength and consistency of this relationship should be confirmed through well-designed association studies. Comparing the prevalence of these mutations in patients who have experienced ototoxicity (the case group) versus those who have not (the control group) would help establish the clinical relevance of screening for these genetic markers. Without the support of rigorous case-control analyses, the claim that testing for these mtDNA mutations has clear clinical utility remains tentative. Additional evidence is needed to determine how effectively these genetic markers can predict an individual’s susceptibility to ototoxicity and how this information should be incorporated into patient management strategies. Overall, a genetic testing panel assessing these key genetic markers could provide valuable information to guide personalized cisplatin dosing and ototoxicity risk management in cancer patients. This could help preserve hearing function and quality of life for those undergoing platinum-based chemotherapy.
In addition to nuclear gene variants, mutations in the mtDNA can also confer increased susceptibility to ototoxicity. The most well-studied mtDNA mutations linked to ototoxicity are the m.1555A>G and m.1494C>T variants in the 12S rRNA gene. These mutations have been shown to increase an individual’s risk of experiencing hearing loss when exposed to aminoglycoside antibiotics, a class of drugs that are commonly used to treat severe infections. Other mtDNA mutations, such as insertions or deletions at the 961 position, have also been associated with ototoxicity. These genetic variants can impact the overall stability and function of the mitochondrial genome, potentially rendering the hair cells more vulnerable to damage from ototoxic insults. Genetic testing for these key mtDNA mutations could help identify individuals who are at a heightened risk of experiencing ototoxicity, particularly prior to administration of aminoglycoside antibiotics. By incorporating this genetic information into clinical decision-making, healthcare providers can take proactive steps to monitor hearing function, adjust drug dosages, or consider alternative treatment options to help preserve a patient’s hearing. Overall, the evaluation of both nuclear and mitochondrial genetic markers can provide a comprehensive assessment of an individual’s susceptibility to ototoxicity. This personalized genetic approach can optimize drug safety and help mitigate the risk of permanent hearing loss for patients undergoing potentially ototoxic therapies. The existing research suggests a potential role for mtDNA mutation screening in assessing ototoxicity risk. However, confirming the clinical significance of this genetic testing approach will require more comprehensive evaluation through carefully designed association studies. This type of evidence-based approach is essential to fully understand the practical applications of this genetic information in a clinical setting.
The latest advancements in the fields of pharmacogenetics, as well as gene and cell-based therapies for hearing protection and restoration, and their potential clinical applications, have been comprehensively reviewed by Zou et al. (Zou et al., 2024) and Gaafar et al. (Gaafar et al., 2024) . According to these reviews, the primary steps leading to ototoxicity can be summarized as follows: cellular uptake facilitated by both passive and active transport mechanisms, DNA binding, and the subsequent cellular response triggering apoptosis, or programmed cell death. The in-depth analysis of these pathogenic processes provides valuable insights that could inform the development of novel therapeutic strategies to mitigate the devastating impact of ototoxicity. By targeting the key molecular events underlying hair cell damage and loss, researchers aim to pave the way for more effective interventions to preserve and potentially restore hearing function in affected patients (Lala et al., 2013).
Extensive research using both in vitro and in vivo models has demonstrated that the primary transporters responsible for cisplatin uptake, namely CTR1 and OCT2, can be pharmacologically modulated. This approach allows for the selective reduction of cisplatin-induced ototoxicity without compromising the drug’s antitumor efficacy. By targeting and regulating the activity or expression of these key cisplatin transporter proteins, it may be possible to limit the accumulation of the cytotoxic drug within the sensitive hair cells of the inner ear, while maintaining its therapeutic levels within the tumor cells. This strategic manipulation of cisplatin’s transport mechanisms represents a promising avenue for developing more targeted and otoprotective treatment strategies. Leveraging this pharmacological insight could help mitigate the devastating hearing loss often associated with cisplatin chemotherapy, without undermining its critical role in cancer treatment (Wang et al., 2023; Pasquariello et al., 2021).
Amifostine, a cytoprotective agent used in chemotherapy regimens involving DNA-binding drugs, was a natural candidate for mitigating the ototoxicity associated with cisplatin treatment. However, the available evidence has not conclusively demonstrated that amifostine can effectively prevent serious SNHL from occurring (Mukherjea et al., 2020; Kessler et al., 2024; Reynard and Thai-Van, 2024). Another compound that has been investigated for its potential protective effects against cisplatin-induced toxicity is diethyldithiocarbamate (and its metabolite, disulfiram); As a thiol-containing molecule, it is thought to exert its protective mechanism by chelating and eliminating cisplatin that has accumulated within tissues, a concept explored in randomized clinical trials conducted in adult patients to prevent cisplatin-induced SNHL (Pfaff et al., 2020). However, the findings from these studies did not demonstrate any significant auditory preservation with the use of this compound. Additionally, no differences were reported in terms of response rate, time to disease progression, or median survival when compared to control groups. Further research has delved into the mechanisms underlying ototoxicity, with a general consensus emerging that the final common pathway leading to hair cell death involves the activation of caspases, a family of proteolytic enzymes that initiate and execute the process of apoptosis, or programmed cell death. This improved understanding of the apoptotic cascades triggered by ototoxic drugs, such as cisplatin, provides valuable insights that can guide the development of targeted interventions to disrupt these detrimental pathways and potentially protect against hearing loss in cancer patients undergoing chemotherapy (Tang et al., 2024). The tumor suppressor protein p53 plays a pivotal upstream role in the mitochondrial-mediated apoptotic pathway. Downregulation or inhibition of the p53 gene has been shown to protect hair cells from a cascade of events, including the translocation of Bcl-2 family members, activation of caspase-3, cytochrome c release, and ultimately, cell death. Based on this understanding, various therapeutic strategies have been proposed to safeguard hair cells against cisplatin-induced apoptosis. These include the use of caspase inhibitors, direct p53 inhibitors, overexpression of the anti-apoptotic protein Bcl-2, and the application of compounds like epigallocatechin-3-gallate (EGCG), which can shift the balance of Bcl-2 family members towards the anti-apoptotic direction by inhibiting the signal transducer and activator of transcription 1 (STAT1) pathway. By targeting key nodes within the apoptotic signaling cascade, these interventions aim to disrupt the detrimental cellular events that lead to hair cell death and the subsequent SNHL associated with cisplatin chemotherapy. Continued research in this area holds promise for developing more effective otoprotective strategies to preserve auditory function in cancer patients (Kim et al., 2012; Monroe et al., 2019; Niu et al., 2021). The c-Jun N-terminal kinases (JNKs) are well-established signaling molecules that play a central role in the regulation of apoptotic pathways. These kinases become activated in response to various forms of cellular stress and damage. Notably, the activation of JNKs occurs upstream of the pivotal events leading to apoptosis, including the redistribution of cytochrome c and the subsequent activation of caspase enzymes. This positioning within the apoptotic cascade suggests that pharmacological inhibition of JNKs could potentially mitigate hair cell loss following exposure to ototoxic agents, such as aminoglycosides. By intercepting the JNK-mediated signaling that ultimately drives programmed cell death, targeted JNK inhibitors may offer a promising avenue for protecting auditory hair cells and preserving hearing function in the context of ototoxicity. This therapeutic strategy aims to disrupt the detrimental cellular cascades that culminate in hair cell demise, thereby safeguarding the critical sensory structures of the inner ear (Jiang et al., 2006; Abi-Hachem et al., 2010).
Ladrech et al. conducted research demonstrating that the initiation of the intrinsic, mitochondria-mediated apoptotic pathway is a key mechanism underlying cisplatin-induced hair cell death (Wang et al., 2004). Specifically, they observed the activation of caspase-9 and caspase-3, two critical effector enzymes within this apoptotic cascade, in guinea pig hair cells following cisplatin exposure. Importantly, the researchers were able to show that the use of specific inhibitors targeting these caspase enzymes, such as z-LEHD-fmk for caspase-9 and z-DEVD-fmk for caspase-3, can effectively protect sensory hair cells from cisplatin-induced loss when applied in cochlear explant models. Notably, this pharmacological intervention not only preserved the structural integrity of the hair cells but also conferred protective effects on hearing function. These findings highlight the pivotal role of caspase-mediated apoptosis in cisplatin ototoxicity and suggest that targeted inhibition of these pro-apoptotic enzymes may represent a promising therapeutic strategy to mitigate hearing loss associated with cisplatin chemotherapy. By selectively disrupting the terminal steps of the apoptotic cascade, caspase inhibitors have the potential to safeguard the critical auditory sensory cells and maintain hearing capacity in cancer patients undergoing cisplatin-based treatment regimens (Wang et al., 2004).
Unlike the caspase enzymes primarily involved in driving the execution of apoptosis, caspase-1 has a distinct role in mediating inflammatory responses through the regulation of inflammatory mediators (Shi et al., 2015). Notably, the application of caspase-1 inhibitors, such as Ac-VAD-cmk, has been shown to protect against cisplatin-induced hair cell apoptosis in neonatal rat cochlear explant models. In addition to the caspase-1 pathway, emerging research has identified cyclin-dependent kinase 2 (CDK2) as a promising therapeutic target for mitigating cisplatin-induced ototoxicity (Hazlitt et al., 2018). CDK2 inhibitors have demonstrated the ability to safeguard against cisplatin-mediated hair cell death, potentially through mechanisms involving the modulation of ROS and the suppression of caspase-3/7 activation. These findings suggest that targeting distinct inflammatory and cell cycle-related pathways, in addition to the apoptotic cascades involving caspase-3 and caspase-9, may provide multifaceted approaches to protecting the delicate auditory sensory structures from the damaging effects of cisplatin chemotherapy. Further investigation into the complex interplay of these various signaling mechanisms could guide the development of more comprehensive otoprotective interventions to preserve hearing function in cancer patients (Liu et al., 1998).
The available research suggests that certain natural compounds and pharmaceutical agents may have the potential to mitigate the adverse effects of the chemotherapeutic drug cisplatin on hearing function. Specifically, the green tea polyphenol EGCG has been shown to offer protection against cisplatin-induced hearing loss in animal models. This protective effect appears to be associated with EGCG’s ability to modulate the expression of the apoptosis-related proteins Bax and Bcl-xL. Similarly, the blue-green algae pigment C-phycocyanin has been found to help maintain the levels of Bax and Bcl-2 proteins close to HEI-OC1 that were exposed to cisplatin, indicating a protective role against cisplatin’s cytotoxic effects (Borse et al., 2017). Furthermore, the antibiotic minocycline, a tetracycline derivative commonly used to treat acne, has been reported to have a protective influence against cisplatin-induced ototoxicity in guinea pigs. This protective effect was linked to an increase in the activity of the anti-apoptotic protein Bcl-2 (Borse et al., 2017; Lee et al., 2011). This suggests that interfering with the mitochondrial Bcl-2 family protects cells from cisplatin-induced ototoxicity (Shinde et al., 2018).
While significant progress has been made in understanding the genetic basis of ototoxicity, several challenges remain that warrant further investigation and innovative approaches. Firstly, the complexity of the genetic landscape underlying ototoxicity presents a significant challenge. Numerous genetic variants, both in nuclear and mtDNA, have been implicated in conferring susceptibility or resistance to ototoxic drugs. Elucidating the precise mechanisms by which these genetic factors influence auditory function and drug response is an ongoing area of research. Employing advanced techniques, such as genome-wide association studies and next-generation sequencing, can help uncover additional genetic markers and shed light on the intricate interplay between multiple genes and ototoxicity. Secondly, the clinical implementation of pharmacogenomic testing for ototoxicity risk assessment faces practical hurdles. Integrating genetic testing into routine clinical practice requires overcoming barriers related to cost, accessibility, and the interpretation of genetic data. Developing robust, validated, and cost-effective genetic screening panels that can be easily implemented in healthcare settings is crucial for widespread adoption. Furthermore, the translation of genetic findings into personalized prevention and management strategies for ototoxicity remains a challenge. Robust clinical studies are needed to establish the predictive value of genetic markers and determine how best to incorporate this information into clinical decision-making. This includes evaluating the utility of genetic testing in guiding drug dosing, monitoring, and the selection of alternative therapies to mitigate ototoxic risks. Looking to the future, interdisciplinary collaborations between clinicians, geneticists, and pharmacologists will be essential to advance the field of ototoxicity pharmacogenomics. Establishing multinational, diverse patient cohorts and harmonizing data collection and analysis methods can facilitate larger-scale, multi-center studies. These efforts will be critical in validating the clinical utility of genetic testing and developing evidence-based guidelines for the prevention and management of ototoxicity. Additionally, exploring the potential of novel therapeutic interventions, such as otoprotective agents and gene-based therapies, may provide new avenues for mitigating ototoxicity. Integrating these emerging approaches with personalized pharmacogenomic strategies could lead to more comprehensive solutions for preserving auditory function in patients undergoing potentially ototoxic treatments.
In conclusion, the genetic basis of ototoxicity presents both challenges and opportunities for healthcare professionals. Addressing the complexities of the genetic landscape, facilitating the clinical implementation of pharmacogenomic testing, and translating research findings into personalized prevention and management strategies will be crucial steps in advancing this rapidly evolving field. Collaborative efforts and continued research will be instrumental in empowering clinicians to better protect patients’ hearing and improve overall quality of life.
Conflict of interestThe authors declare that there is no conflict of interest.
