Cisplatin-induced Hearing Loss Research Articles

The Antioxidant Ergothioneine Alleviates Cisplatin-Induced Hearing Loss through the Nrf2 Pathway.

Aims: Cisplatin (CDDP) is a commonly used chemotherapeutic agent for treating head and neck tumors. However, there is high incidence of ototoxicity in patients treated with CDDP, which may be caused by the excessive reactive oxygen species (ROS) generation in the inner ear. Many studies have demonstrated the strong antioxidant effects of ergothioneine (EGT). Therefore, we assumed that EGT could also attenuate cisplatin-induced hearing loss (CIHL) as well. However, the protective effect and mechanism of EGT on CIHL have not been elucidated as so far. In this study, we investigated whether EGT could treat CIHL and the mechanism. Results: In our study, we confirmed the protective effect of EGT on preventing CDDP-induced toxicity both in vitro and invivo. The auditory brainstem response threshold shift in the EGT + CDDP treatment mice was 30 dB less than that in the CDDP treatment mice. EGT suppressed production of ROS and proapoptotic proteins both in tissue and cells. By silencing nuclear factor erythroid 2-related factor 2 (Nrf2), we confirmed that EGT protected against CIHL via the Nrf2 pathway. We also found that SLC22A4 (OCTN1), an important molecule involved in transporting EGT, was expressed in the cochlea. Innovation: Our results revealed the role of EGT in the prevention of CIHL by activating Nrf2/HO-1/NQO-1 pathway, and broadened a new perspective therapeutic target of EGT. Conclusion: EGT decreased ROS production and promoted the expression of antioxidative enzymes to maintain redox homeostasis in sensory hair cells. Overall, our results indicated that EGT may serve as a novel treatment drug to attenuate CIHL.

Use of Sodium Thiosulfate as an Otoprotectant in Patients With Cancer Treated With Platinum Compounds: A Review of the Literature.

Hearing loss occurs in 50%-70% of children treated with cisplatin. Scientific efforts have led to the recent approval of a pediatric formula of intravenous sodium thiosulfate (STS) for otoprotection by the US Food and Drug Administration, the European Medicines Agency, and the Medicines and Health Regulatory Authority in the United Kingdom. To inform stakeholders regarding the clinical utility of STS, the current review summarizes available literature on the efficacy, pharmacokinetics (PK), and safety of systemic STS to minimize cisplatin-induced hearing loss (CIHL). A comprehensive narrative review is presented. Thirty-one articles were summarized. Overall, systemic STS effectively reduces CIHL in the preclinical and controlled clinical study settings, in both adults and children with cancer. The extent of CIHL reduction depends on the timing and dosing of STS in relation to cisplatin. Both preclinical and clinical data suggest that systemic STS may affect plasma platinum levels, but studies are inconclusive. Delayed systemic administration of STS, at 6 hours after the cisplatin infusion, does not affect cisplatin-induced inhibition of tumor growth or cellular cytotoxicity in the preclinical setting, nor affect cisplatin efficacy and survival in children with localized disease in the clinical setting. Systemic administration of STS effectively reduces the development and degree of CIHL in both the preclinical and clinical settings. More studies are needed on the PK of STS and cisplatin drug combinations, the efficacy and safety of STS in patients with disseminated disease, and the ability of STS to prevent further deterioration of pre-established hearing loss.

FDA-Approved Tedizolid Phosphate Prevents Cisplatin-Induced Hearing Loss Without Decreasing Its Anti-tumor Effect.

Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs. Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin. Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs. Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.

Quantum chemistry calculation-aided discovery of potent small-molecule mimics of glutathione peroxidases for the treatment of cisplatin-induced hearing loss

Hearing loss (HL) is a health burden that seriously affects the quality of life of cancer patients receiving platinum-based chemotherapy, and few FDA-approved treatment specifically targets this condition. The main mechanisms that contribute to cisplatin-induced hearing loss are oxidative stress and subsequent cell death, including ferroptosis revealed by us as a new mechanism recently. In this study, we employed the frontier molecular orbital (FMO) theory approach as a convenient prediction method for the glutathione peroxidase (GPx)-like activity of isoselenazolones and discovered new isoselenazolones with great GPx-like activity. Notably, compound 19 exhibited significant protective effects against cisplatin-induced hair cell (HC) damage in vitro and in vivo and effectively reverses cisplatin-induced hearing loss through oral administration. Further investigations revealed that this compound effectively alleviated hair cell oxidative stress, apoptosis and ferroptosis. This research highlights the potential of GPx mimics as a therapeutic strategy against cisplatin-induced hearing loss. The application of quantum chemistry (QC) calculations in the study of GPx mimics sheds light on the development of new, innovative treatments for hearing loss.

Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis

Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.

Combined genetic polymorphisms of the GSTT1 and NRF2 genes increase susceptibility to cisplatin-induced ototoxicity: A preliminary study

ObjectiveThe genotype-phenotype relationship in cisplatin-induced ototoxicity remains unclear. By assessing early shifts in distortion product otoacoustic emission (DPOAE) levels after initial cisplatin administration, we aimed to discriminate patients’ susceptibility to cisplatin-induced ototoxicity and elucidate their genetic background. Study DesignA prospective cross-sectional study. SettingTertiary referral hospital in Japan. PatientsTwenty-six patients with head and neck cancer were undergoing chemoradiotherapy with three cycles of 100 mg/m2 cisplatin. InterventionsRepetitive pure-tone audiometry and DPOAE measurements, and blood sampling for DNA extraction were performed. Patients were grouped into early ototoxicity presence or absence based on whether DPOAE level shifts exceeded the corresponding reference limits of the 21-day test interval. Main Outcome MeasuresHearing thresholds after each cisplatin cycle, severity of other adverse events, and polymorphisms in cisplatin-induced ototoxicity-associated genes were compared. ResultsEarly ototoxicity was present in 14 and absent in 12 patients. Ototoxicity presence on DPOAEs was associated with greater progression of hearing loss in frequencies ≥2 kHz throughout therapy and with higher ototoxicity grades compared with ototoxicity absence. Ototoxicity was further associated with grade ≥2 nausea. Ototoxicity presence was genetically associated with the GSTT1 null genotype and G-allele of NFE2L2 rs6721961, whereas ototoxicity absence was associated with the GSTM1 null genotype. Dose-dependent progression of hearing loss was the greatest in the combined genotype pattern of GSTT1 null and the T/G or G/G variants of rs6721961. ConclusionEarly DPOAE changes reflected genetic vulnerability to cisplatin-induced ototoxicity. Hereditary insufficiency of the antioxidant defense system causes severe cisplatin-induced hearing loss and nausea.

4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway.

Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research has suggested that in cisplatin-mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4-Octyl itaconate (4-OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti-inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4-OI on cisplatin-induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI-OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH-DA. Real-time PCR quantified inflammatory cytokines TNF-α, IL-6 and IL-1β. Network Pharmacology and RNA sequencing (RNA-seq) analysis of the potential mechanism of 4-OI resistance to cisplatin-induced ferroptosis. The expressions of ferroptosis-related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO-1, GCLC and NQO1) were tested by real-time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin-induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4-OI exhibited anti-inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin-induced cell loss. In the present study, we show that 4-OI inhibits cisplatin-induced ferroptosis possibly through activation of the NRF2/HO-1 signalling pathway, thereby exerting a protective effect against cisplatin-induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin-induced hearing loss.

Prevention of cisplatin-induced hearing loss in children: achievements and challenges for evidence-based implementation of sodium Thiosulfate.

Ototoxicity is a devastating direct, irreversible side effect of platinum use in children with cancer, with its consequent effect on speech, language and social development, quality of life and adult productivity. Cisplatin, an essential chemotherapeutic agent for the treatment of solid tumors in children, is a DNA cross-linking agent. Which causes hearing loss in 50-70% of cisplatin treated children. Fortunately, to prevent hearing loss, sodium thiosulfate (STS), which binds to cisplatin, and reduces the superoxides in both tumor and outer hair cells of the cochlea has now been discovered to be an effective and safe otoprotectant if administered correctly. The aim of this perspective paper is to explore the key safety issues and challenges important for pediatric oncologists and pharmacists when considering the clinical use of STS as an otoprotectant for children and adolescents receiving cisplatin. These include: the choice of the formulation; the timing, both that of the STS in relation to cisplatin as well as the timing of the cisplatin infusion itself; the dosing; the challenge left by the definition of localized versus disseminated disease and the difference in indication for STS, between cisplatin treated patients and those receiving another platinum chemotherapeutic agent, carboplatin.

Inhibition of CISD1 attenuates cisplatin-induced hearing loss in mice via the PI3K and MAPK pathways

Cisplatin is an effective chemotherapeutic drug for different cancers, but it also causes severe and permanent hearing loss. Oxidative stress and mitochondrial dysfunction in cochlear hair cells (HCs) have been shown to be important in the pathogenesis of cisplatin-induced hearing loss (CIHL). CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) plays a critical role in mitochondrial oxidative capacity and cellular bioenergetics. Targeting CISD1 may improve mitochondrial function in various diseases. However, the role of CISD1 in cisplatin-induced ototoxicity is unclear. Therefore, this study was performed to assess the role of CISD1 in cisplatin-induced ototoxicity. We found that CISD1 expression was significantly increased after cisplatin treatment in both HEI-OC1 cells and cochlear HCs. Moreover, pharmacological inhibition of CISD1 with NL-1 inhibited cell apoptosis and reduced mitochondrial reactive oxygen species accumulation in HEI-OC1 cells and cochlear explants. Inhibition of CISD1 with small interfering RNA in HEI-OC1 cells had similar protective effects. Furthermore, NL-1 protected against CIHL in adult C57 mice, as evaluated by the auditory brainstem response and immunofluorescent staining. Mechanistically, RNA sequencing revealed that NL-1 attenuated CIHL via the PI3K and MAPK pathways. Most importantly, NL-1 did not interfere with the antitumor efficacy of cisplatin. In conclusion, our study revealed that targeting CISD1 with NL-1 reduced reactive oxygen species accumulation, mitochondrial dysfunction, and apoptosis via the PI3K and MAPK pathways in HEI-OC1 cell lines and mouse cochlear explants in vitro, and it protected against CIHL in adult C57 mice. Our study suggests that CISD1 may serve as a novel target for the prevention of CIHL.

Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice

Cisplatin-induced hearing loss is a common side effect of cancer chemotherapy in clinics, however, the mechanism of cisplatin-induced ototoxicity is still not completely clarified. Cisplatin-induced ototoxicity is mainly associated with the production of reactive oxygen species, activation of apoptosis, and accumulation of intracellular lipid peroxidation, which also is involved in ferroptosis induction. In this study, the expression of TfR1, a ferroptosis biomarker, was upregulated in the outer hair cells of cisplatin-treated mice. Moreover, several key ferroptosis regulator genes were altered in cisplatin-damaged cochlear explants based on RNA-Seq, implying the induction of ferroptosis. Ferroptosis-related Gpx4 and Fsp1 knockout mice were established to investigate the specific mechanisms associated with ferroptosis in cochleae. Severe OHC loss and progressive damage of synapses in IHC were observed in Atoh1-Gpx4-/- mice. However, Fsp1-/- mice showed no significant hearing phenotype, demonstrating that Gpx4, but not Fsp1, may play an important role in the functional maintenance of HCs. Moreover, findings showed that FDA-approved luteolin could specifically inhibit ferroptosis and alleviate cisplatin-induced ototoxicity through decreased expression of Transferrin and intracellular concentration of ferrous ions. This study indicated that ferroptosis inhibition through the reduction of intracellular ferrous ions might be a potential strategy to prevent cisplatin-induced hearing loss.

Protection from cisplatin-induced hearing loss with lentiviral vector-mediated ectopic expression of the anti-apoptotic protein BCL-XL

Cisplatin is a highly effective chemotherapeutic agent, but it can cause sensorineural hearing loss (SNHL) in patients. Cisplatin-induced ototoxicity is closely related to the accumulation of reactive oxygen species (ROS) and subsequent death of hair cells (HCs) and spiral ganglion neurons (SGNs). Despite various strategies to combat ototoxicity, only one therapeutic agent has thus far been clinically approved. Therefore, we have developed a gene therapy concept to protect cochlear cells from cisplatin-induced toxicity. Self-inactivating lentiviral (LV) vectors were used to ectopically express various antioxidant enzymes or anti-apoptotic proteins to enhance the cellular ROS scavenging or prevent apoptosis in affected cell types. In direct comparison, anti-apoptotic proteins mediated a stronger reduction in cytotoxicity than antioxidant enzymes. Importantly, overexpression of the most promising candidate, Bcl-xl, achieved an up to 2.5-fold reduction in cisplatin-induced cytotoxicity in HEI-OC1 cells, phoenix auditory neurons, and primary SGN cultures. BCL-XL protected against cisplatin-mediated tissue destruction in cochlear explants. Strikingly, invivo application of the LV BCL-XL vector improved hearing and increased HC survival in cisplatin-treated mice. In conclusion, we have established a preclinical gene therapy approach to protect mice from cisplatin-induced ototoxicity that has the potential to be translated to clinical use in cancer patients.

Dabrafenib protects from cisplatin-induced hearing loss in a clinically relevant mouse model.

The widely used chemotherapy cisplatin causes permanent hearing loss in 40%-60% of patients with cancer. One drug, sodium thiosulfate, is approved by the FDA for use in pediatric patients with localized solid tumors for preventing cisplatin-induced hearing loss, but more drugs are desperately needed. Here, we tested dabrafenib, an FDA-approved BRAF kinase inhibitor and anticancer drug, in a clinically relevant multidose cisplatin mouse model. The protective effects of dabrafenib, given orally twice daily with cisplatin, were determined by functional hearing tests and cochlear outer hair cell counts. Toxicity of the drug cotreatment was evaluated, and levels of phosphorylated ERK were measured. A dabrafenib dose of 3 mg/kg BW, twice daily, in mice, was determined to be the minimum effective dose, and it is equivalent to one-tenth of the daily FDA-approved dose for human cancer treatment. The levels of hearing protection acquired, 20-25 dB at the 3 frequencies tested, in both female and male mice, persisted for 4 months after completion of treatments. Moreover, dabrafenib exhibited a good in vivo therapeutic index (> 25), protected hearing in 2 mouse strains, and diminished cisplatin-induced weight loss. This study demonstrates that dabrafenib is a promising candidate drug for protection from cisplatin-induced hearing loss.

Drug screening identifies aldose reductase as a novel target for treating cisplatin-induced hearing loss

Cisplatin is a frequently used chemotherapeutic medicine for cancer treatment. Permanent hearing loss is one of the most serious side effects of cisplatin, but there are few FDA-approved medicines to prevent it. We applied high-through screening and target fishing and identified aldose reductase, a key enzyme of the polyol pathway, as a novel target for treating cisplatin ototoxicity. Cisplatin treatment significantly increased the expression level and enzyme activity of aldose reductase in the cochlear sensory epithelium. Genetic knockdown or pharmacological inhibition of aldose reductase showed a significant protective effect on cochlear hair cells. Cisplatin-induced overactivation of aldose reductase led to the decrease of NADPH/NADP+ and GSH/GSSG ratios, as well as the increase of oxidative stress, and contributed to hair cell death. Results of target prediction, molecular docking, and enzyme activity detection further identified that Tiliroside was an effective inhibitor of aldose reductase. Tiliroside was proven to inhibit the enzymatic activity of aldose reductase via competitively interfering with the substrate-binding region. Both Tiliroside and another clinically approved aldose reductase inhibitor, Epalrestat, inhibited cisplatin-induced oxidative stress and subsequent cell death and thus protected hearing function. These findings discovered the role of aldose reductase in the pathogenesis of cisplatin-induced deafness and identified aldose reductase as a new target for the prevention and treatment of hearing loss.

Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions.

Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40-60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years.

Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI.

To combat both untoward effects of nephrotoxicity and ototoxicity in cisplatin-treated patients, two potential therapeutic oral anticancer drugs AZD5438 and dabrafenib, a phase-2 clinical trial protein kinase CDK2 inhibitor and an US Food and Drug Administration-approved drug BRAF inhibitor, respectively, were tested in an established mouse AKI model. Both drugs have previously been shown to protect significantly against cisplatin-induced hearing loss in mice. Each drug ameliorated cisplatin-induced increases in the serum biomarkers BUN, creatinine, and neutrophil gelatinase-associated lipocalin. Drugs also improved renal histopathology and inflammation, mitigated cell death by pyroptosis and necroptosis, and significantly enhanced overall survival of cisplatin-treated mice. Cisplatin is an effective chemotherapy agent for a wide variety of solid tumors, but its use is dose-limited by serious side effects, including AKI and hearing loss. There are no US Food and Drug Administration-approved drugs to treat both side effects. Recently, two anticancer oral drugs, AZD5438 and dabrafenib, were identified as protective against cisplatin-induced hearing loss in mice. We hypothesize that similar cell stress and death pathways are activated in kidney and inner ear cells when exposed to cisplatin and tested whether these drugs alleviate cisplatin-induced AKI. The HK-2 cell line and adult FVB mice were used to measure the protection from cisplatin-induced cell death and AKI by these drugs. Serum markers of kidney injury, BUN, creatinine, and neutrophil gelatinase-associated lipocalin as well as histology of kidneys were analyzed. The levels of markers of kidney cell death, including necroptosis and pyroptosis, pERK, and proliferating cell nuclear antigen, were also examined by Western blotting and immunofluorescence. In addition, CDK2 knockout (KO) mice were used to confirm AZD5438 protective effect is through CDK2 inhibition. The drugs reduced cisplatin-induced cell death in the HK-2 cell line and attenuated cisplatin-induced AKI in mice. The drugs reduced serum kidney injury markers, inhibited cell death, and reduced the levels of pERK and proliferating cell nuclear antigen, all of which correlated with prolonged animal survival. CDK2 KO mice were resistant to cisplatin-induced AKI, and AZD5438 conferred no additional protection in the KO mice. Cisplatin-induced damage to the inner ear and kidneys shares similar cellular beneficial responses to AZD5438 and dabrafenib, highlighting the potential therapeutic use of these agents to treat both cisplatin-mediated kidney damage and hearing loss.

Circulating IL-17 reduces the risk of cisplatin-induced hearing loss in children: a bidirectional two-sample Mendelian randomization study

Studies have reported that cytokines and their related signaling pathways play a role in inner ear diseases. In clinical practice, approximately 50% of pediatric cancer patients experience irreversible hearing loss after cisplatin treatment. However, currently, there is a lack of systematic research on the causal relationship between circulating cytokines and cisplatin-induced hearing loss in children. Genetic variant data for 41 circulating cytokines were obtained from a meta-analysis of genome-wide association studies (GWAS) among 8293 individuals of Finnish descent. The GWAS data for Cisplatin-induced hearing loss in children were derived from a multicenter cohort of European pediatric cancer patients and survivors (N = 390), including both cases with hearing loss after cisplatin chemotherapy and controls without hearing loss. Multiple methods were employed for bidirectional Mendelian randomization (MR) estimation. Bonferroni correction was applied to adjust the original P-values, followed by a series of sensitivity analyses. In the directional Mendelian randomization (MR) analysis, it was found that IL-17 was significantly associated with a reduced risk of Cisplatin-induced hearing loss in children (OR: 0.18, CI: 0.06–0.48, P < 0.001, FDR = 0.041). In the reverse MR analysis, there were some nominal causal relationships of Cisplatin-induced hearing loss in children with certain cytokines [M-CSF: (OR: 1.04, CI: 1.01–1.08, P = 0.010, FDR = 0.41); IL-2RA: (OR: 1.03, CI: 1.00–1.05, P = 0.044, FDR = 0.447); MIP-1β: (OR: 1.02, CI: 1.00–1.04, P = 0.041, FDR = 0.447)]. leave-one-out analysis demonstrated that only M-CSF exhibited stability. These findings reveal a causal relationship between IL-17 and cisplatin-induced hearing loss in children. Further research is needed to determine the potential protective mechanisms of IL-17 in cisplatin-induced ototoxicity.

CORM‑2 reduces cisplatin accumulation in the mouse inner ear and protects against cisplatin-induced ototoxicity

IntroductionCisplatin is a life-saving anticancer compound used to treat multiple solid malignant tumors, while it causes permanent hearing loss. There is no known cure, and the FDA has not approved any preventative treatment for cisplatin-based ototoxicity. ObjectivesThis study investigated whether the carbon monoxide (CO)-releasing tricarbonyldichlororuthenium (II) dimer, CORM-2, reverses cisplatin-induced hearing impairment and reduces cisplatin accumulation in the mouse inner ear. MethodsMale 6-week-old BALB/c mice were randomly assigned to one of the following groups: control (saline-treated, i.p.), CORM-2 only (30 mg/kg, i.p., four doses), cisplatin only (20 mg/kg, i.p., one dose), and CORM-2 + cisplatin, to determine whether cisplatin-based hearing impairment was alleviated by CORM-2 treatment. ResultsOur results revealed CORM-2 significantly attenuated cisplatin-induced hearing loss in young adult mice. CORM-2 co-treatment significantly decreased platinum accumulation in the inner ear and activated the plasma membrane repair system of the stria vascularis. Moreover, CORM-2 co-treatment significantly decreased cisplatin-induced inflammation, apoptosis, and cochlear necroptosis. Because the stria vascularis is the likely cochlear entry point of cisplatin, we next focused on the microvasculature. Cisplatin induced increased extravasation of a chromatic tracer (fluorescein isothiocyanate [FITC]-dextran, MW 75 kDa) around the cochlear microvessels at 4 days post-treatment; this extravasation was completely inhibited by CORM-2 co-therapy. CORM-2 co-treatment effectively maintained the integrity of stria vascularis components including endothelial cells, pericytes, and perivascular-resident macrophage-type melanocytes. ConclusionCORM-2 co-therapy substantially protects against cisplatin-induced ototoxicity by reducing platinum accumulation and toxic cellular stress responses. These data indicate that CORM-2 co-treatment may be translated into clinical strategy to reduce cisplatin-induced hearing loss.

Incidence of cisplatin-induced ototoxicity in adult cancer patients based on audiometric confirmation of patient self-report

IntroductionRobust clinically relevant epidemiological and audiological data are needed to prepare for future clinical trials aiming at preventing cisplatin-induced ototoxicity in this suffering cancer population. We assessed the incidence, severity, and potential risk factors of symptomatic cisplatin-induced hearing loss in a large cohort of adults.MethodsRetrospective cohort study at a tertiary care university hospital. The study group included consecutive patients over 18 years old treated with cisplatin-based chemotherapy without concomitant inner ear radiotherapy or other ototoxic medication. Every participant underwent baseline pretreatment audiometry and was asked for audiological symptoms (tinnitus or subjective hearing loss) during the treatment. If symptomatic, comparative standard audiometry (0.125 to 8 kHz) was performed. Hearing loss was defined by a threshold shift ≥15 dB HL in at least one of the tested frequencies.ResultsA total of 401 cancer patients (59% males) with a mean age of 56 years (range 18-80) were included. Eighty-one patients (20%) developed symptomatic hearing loss, predominantly affecting the high frequencies from 4 to 8 kHz. Among them, 49 (60%) experienced simultaneous new-onset tinnitus. None of the analyzed potential risk factors (age, sex, smoking, hypertension, diabetes, dyslipidemia, chemotherapeutic regimen, and cumulative cisplatin dose) was statistically correlated with hearing loss.DiscussionAt least 1 out of 5 patients treated with cisplatin developed audiological symptoms associated with audiometric hearing loss within the 0.125 to 8 kHz range, for which new-onset tinnitus is a sensitive symptom. Not all audiological symptoms are accompanied by audiometric change. No predisposing factor could be identified. Standardized audiological monitoring before and during cisplatin-based chemotherapy allows quantitative assessment of early audiometric signs of ototoxicity, offering to optimize anticancer therapy while minimizing morbidity in a multidisciplinary setting.

Intratympanic Dexamethasone Role in Hearing Protection in Cancer Patients.

Introduction The study aims to determine the role of intratympanic dexamethasone (ITD) on the hearing profile of patients with head and neck cancer post-chemoradiotherapy. Study design This study employs a prospective case-control design. Subjects and methods In total 834 patients were evaluated for eligibility. Seven hundred and elevenwere excluded because they didn't meet the inclusion criteria. A hundred cases out of 123 were diagnosed with head and neck cancer for which the treatment protocol included cisplatin concurrent to radiotherapy recruited. Before each cisplatin treatment session, ITD was injected into one ear (experimental ear) while the other ear of the same patient served as the control. Pure-tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAE) test results of the baseline and follow-up examinations in the sixth and 12th weeks were compared within and between the study and control ears. Results For pure tone thresholds, significant hearing threshold change was noticed at 8 kHz in the experimental group at six weeks and at ≥ 6 kHz in the control group. At 12 weeks, high frequencies were significantly affected at ≥ 4 kHz in the control group. When the baseline was compared across the groups in the 12th week, for otoacoustic emissions, high frequencies showed a loss in the control group more compared to the experimental side (Wilcoxon signed-rank test). Conclusion ITD functions less effectively at higher frequencies because the basal turn of the cochlea is more susceptible to cisplatin ototoxicity. ITD might have potential in the reduction of cisplatin-induced hearing loss.

Predicting Hearing Loss in Testicular Cancer Patients after Cisplatin-Based Chemotherapy.

Testicular cancer is predominantly curable, but the long-term side effects of chemotherapy have a severe impact on life quality. In this research study, we focus on hearing loss as a part of overall chemotherapy-induced ototoxicity. This is a unique approach where we combine clinical data from the acclaimed nationwide Danish Testicular Cancer (DaTeCa)-Late database. Clinical and genetic data on 433 patients were collected from hospital files in October 2014. Hearing loss was classified according to the FACT/GOG-Ntx-11 version 4 self-reported Ntx6. Machine learning models combining a genome-wide association study within a nested cross-validated logistic regression were applied to identify patients at high risk of hearing loss. The model comprising clinical and genetic data identified 67% of the patients with hearing loss; however, this was with a false discovery rate of 49%. For the non-affected patients, the model identified 66% of the patients with a false omission rate of 19%. An area under the receiver operating characteristic (ROC-AUC) curve of 0.73 (95% CI, 0.71-0.74) was obtained, and the model suggests genes SOD2 and MGST3 as important in improving prediction over the clinical-only model with a ROC-AUC of 0.66 (95% CI, 0.65-0.66). Such prediction models may be used to allow earlier detection and prevention of hearing loss. We suggest a possible biological mechanism for cisplatin-induced hearing loss development. On confirmation in larger studies, such models can help balance treatment in clinical practice.