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Biomedicine & Pharmacotherapy =... Sep 2023Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side...
Oxaliplatin, as a third-generation platinum-based anticancer drug, is widely used in tumor therapy of many systems. Clinically, oxaliplatin has a number of serious side effects, most notably neuropathy and ototoxicity. The degeneration of cochlear hair cells is the main reason for the hearing loss caused by platinum-based drugs. However, the mechanism of oxaliplatin-induced cochlear hair cell death remains unclear. Ferroptosis is a novel cell injury pattern triggered by the accumulation of iron hydroperoxides in lipids and dependent on the participation of iron ions, which plays an important role in a variety of diseases. Whether ferroptosis is involved in oxaliplatin-induced ototoxicity has not been reported. In this study, we observed that oxaliplatin treatment resulted in lipid peroxidation and reactive oxygen species (ROS) accumulation in OC1 cells, which may be an early alteration in the occurrence of ferroptosis. Additional treatment with ferroptosis inducer or inhibitor significantly aggravated or ameliorated oxaliplatin-induced cytotoxicity. Similarly, inhibition of ferroptosis also protected cochlear hair cells against oxaliplatin-induced injury. In addition, the expression of nuclear factor erythroid 2-related factor2 (Nrf2) and heme oxygenase-1 (HO-1) was significantly increased after oxaliplatin treatment, and treatment with the Nrf2 agonist, resveratrol, dramatically attenuated cochlear hair cell damage induced by oxaliplatin. Activation of Nrf2 significantly decreased the expression of iron regulatory protein 2 (IRP-2) and reversed the expression of glutathione peroxidase 4 (GPX4). Collectively, our results demonstrated that activation of Nrf2 alleviates oxaliplatin-induced cochlear hair cell damage by inhibiting ferroptosis, which may be a new mechanism of oxaliplatin-induced ototoxicity.
Topics: Antineoplastic Agents; Ferroptosis; Iron; NF-E2-Related Factor 2; Ototoxicity; Oxaliplatin; Reactive Oxygen Species; Animals; Mice; Cell Line
PubMed: 37523980
DOI: 10.1016/j.biopha.2023.115248 -
Otolaryngologia Polska = the Polish... Jun 2024<b><br>Introduction:</b> Immune checkpoint inhibitors (ICIs) and T-cell therapies are a modern, well-established cancer treatment. The priority of... (Review)
Review
<b><br>Introduction:</b> Immune checkpoint inhibitors (ICIs) and T-cell therapies are a modern, well-established cancer treatment. The priority of oncological treatment is to cure cancer. However, treatment-related toxicities, i.e. immune-related adverse events (irAEs), continue to emerge and are not that well understood yet. ICIs can cause profound, multiple, and diverse irAEs - the sequelae of unknown mechanisms. One of the organs susceptible to collateral damage is the hearing organ. Complications related to hearing, tinnitus, and balance disorders are extremely burdensome and significantly impair many aspects of the quality of life of patients and survivors.</br> <b><br>Aim:</b> The aim of the work is to review the literature in the area of ototoxicity of ICIs.</br> <b><br>Materials and method:</b> A systematic search of the Web of Science, PubMed, and Embase databases for studies published until 1 March 2022 was conducted.</br> <b><br>Results:</b> Reported clinical symptoms ranged from sudden bilateral hearing loss and imbalance to mild hearing loss or tinnitus with preserved hearing. It was found that the median time from ICI initiation to hearing loss development was 3 months. The hearing impairment was secondary to bilateral sensorineural hearing loss in the majority of patients (>60%), and at least one other irAE accompanied the hearing loss in 2/3 of patients. Hearing loss significantly improved in 45.7% of the patients.</br> <b><br>Conclusions:</b> The majority of cases of ICI-related hearing loss presented in the literature were reversible. Therefore, it is important to develop and implement routine therapeutic algorithms. Further research is needed to define the true prevalence of ICI-related hearing loss, optimal diagnostics, and management.</br>.
Topics: Humans; Immune Checkpoint Inhibitors; Ototoxicity; Male; Female; Hearing Loss; Neoplasms; Middle Aged
PubMed: 38808639
DOI: No ID Found -
The Turkish Journal of Pediatrics 2022Hearing is essential in child development. Cisplatin which is a common chemotherapy used in many pediatric solid-tumor protocols cause various degrees of ototoxicity....
BACKGROUND
Hearing is essential in child development. Cisplatin which is a common chemotherapy used in many pediatric solid-tumor protocols cause various degrees of ototoxicity. Several risk factors for cisplatininduced ototoxicity have been reported, including race and age. This study aimed to evaluate the incidence of ototoxicity and its long-term outcome in Thai pediatric solid-tumor patients receiving cisplatin and to determine the risk factors associated with hearing impairment.
METHODS
A retrospective study was conducted in solid-tumor patients < 15 years old from 2007 to 2019 at Siriraj Hospital, Bangkok, Thailand. Hearing was evaluated by an audiogram and/or auditory steady-state response and the impairment was graded according to the Common Terminology Criteria for Adverse Events version 5. Grade 2 and above was considered significant hearing loss.
RESULTS
In total, the hearing of 47 patients was evaluated. At the end of treatment, hearing impairment and significant hearing loss were found in 66% and 48.9% of patients, respectively. A high median cumulative cisplatin dose was significantly associated with worse hearing impairment (p = 0.039) and a more progressive grading of ototoxicity (p = 0.005). A risk factor for significant hearing loss was a cumulative dose ≥400 mg/m2 (p = 0.014). All 9 patients who received a cumulative dose > 600 mg/m2 and 5 patients who received aminoglycoside developed significant hearing loss. One patient had progressive hearing impairment at 8 months after the end of treatment and 1 patient developed grade 3 ototoxicity which required a hearing aid after bone marrow transplantation. The latter patient received a total cisplatin dose of 708.2 mg/m < sup > 2 < /sup > and carboplatin 1400 mg/m < sup > 2 < /sup > .
CONCLUSIONS
The incidence of hearing impairment in pediatric patients receiving cisplatin is high. Regular hearing evaluation is essential for the early detection of ototoxicity. Long-term follow-up is recommended, especially in patients who have a combination of other risk factors for hearing loss.
Topics: Adolescent; Antineoplastic Agents; Child; Cisplatin; Hearing; Hearing Loss; Humans; Neoplasms; Ototoxicity; Retrospective Studies; Thailand
PubMed: 35899566
DOI: 10.24953/turkjped.2021.5012 -
Toxicology Letters Sep 2015Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies... (Review)
Review
Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations.
Topics: Antineoplastic Agents; Cisplatin; Humans; Kidney Diseases; Reactive Oxygen Species; Vestibular Diseases
PubMed: 26101797
DOI: 10.1016/j.toxlet.2015.06.012 -
BioMed Research International 2013INF- α is a common drug for the treatment of hepatitis B and C. Although a variety of related complications are discussed, possible ototoxic effects of this mediation...
INTRODUCTION
INF- α is a common drug for the treatment of hepatitis B and C. Although a variety of related complications are discussed, possible ototoxic effects of this mediation are not well described.
METHODS AND MATERIALS
In a before-after control study, 24 patients who received INF- α for the treatment of hepatitis B and C and 30 normal controls were included. Subjective and objective ototoxicity evaluations via questionnaire, high frequency audiometry, and measuring transiently evoked otoacoustic emissions (TEOAEs) were performed one week before and one month after the prescription of the drug. Results. Subjective hearing complaint, tinnitus, and vertigo were seen in just 3 cases, which was not statistically significant (P = 0.083). In the frequency range of 4000 to 8000 Hz before (9.38 ± 1.0 and 10.7 ± 1.2, resp.) and after (17.9 ± 2.6 and 17.6 ± 2.6, resp.) one month of treatment, a significant difference (P = 0.083) was detected. Progressive decreases in amplitude of the OAE during TEOAE measurement in 1, 2, and 4 frequencies among 41.66%, 18.75 %, and 43.75% were observed, respectively. The hearing loss was seen more among older and male cases significantly. Conclusion. The results showed ototoxicity of INF- α that may encourage planning hearing monitoring in patients receiving this drug.
Topics: Adult; Audiometry, Pure-Tone; Auditory Threshold; Case-Control Studies; Ear Diseases; Female; Hearing Disorders; Humans; Interferon-alpha; Male; Otoacoustic Emissions, Spontaneous; Reflex, Acoustic
PubMed: 23984336
DOI: 10.1155/2013/295327 -
BioMed Research International 2021Cisplatin is an efficacious anticancer agent, but its use is limited by ototoxicity and resultant irreversible sensorineural hearing loss. Cisplatin ototoxicity is...
Cisplatin is an efficacious anticancer agent, but its use is limited by ototoxicity and resultant irreversible sensorineural hearing loss. Cisplatin ototoxicity is associated with cochlear cell oxidative stress and mitochondrial damage. However, mitophagy is vital for maintaining mitochondrial quality and cellular metabolism. Accordingly, we investigated the role of mitophagy in regulating cisplatin-induced ototoxicity using the auditory cell line HEI-OC1. In this study, HEI-OC1 cells were treated with either cisplatin alone (10 M, 0, 8, 16, and 24 h); cisplatin (10 M, 24 h) post transfection with small-interfering (si)RNAs targeting mitophagy-associated mRNAs; cisplatin (10 M, 24 h) succeeding pretreatment with the mitophagy suppressor, 3-methyladenine (3-MA; 5 or 10 mM, 6 h); or cisplatin (30 M, 24 h) following pretreatment with the mitophagy promoter, carbonyl cyanide m-chlorophenylhydrazone (CCCP; 1 or 2 M, 2 h). The viability of cells, expression of mitophagy marker, and mitochondrial functions were then assessed in these cells. Cell viability was determined by a water-soluble tetrazolium assay; expression of mitophagy-associated proteins , , , , p62, and LC3B was analyzed by Western blotting, mitochondrial membrane potential by flow cytometry, intracellular ATP by spectrophotometry, and mitochondrial degradation by dual staining for mitochondria and autophagosomes or lysosomes. Our results showed that cisplatin gradually reduced the viable cell number over time, induced mitochondrial depolarization, decreased intracellular ATP concentration, and enhanced the expression of , , , p62, and LC3B. In addition, and knockdown accelerated cisplatin-induced loss of cell viability, mitochondrial membrane potential, mitophagosome/lysosome formation, and reduction in intracellular ATP production. Pretreatment with 3-MA aggravated the cisplatin-induced cytotoxicity, while that with CCCP reversed this effect. Overall, our findings indicate that mitophagy protects HEI-OC1 cells against cisplatin-induced cell death. Consequently, we strongly believe that targeted promotion of mitophagy may confer protection against cisplatin-induced ototoxicity.
Topics: Apoptosis; Autophagosomes; Cell Line, Tumor; Cell Survival; Cisplatin; Hearing Loss, Sensorineural; Humans; Membrane Potential, Mitochondrial; Membrane Proteins; Mitochondria; Mitophagy; Ototoxicity; Proto-Oncogene Proteins; RNA, Small Interfering; Reactive Oxygen Species; Ubiquitin-Protein Ligases
PubMed: 34095303
DOI: 10.1155/2021/5590973 -
Seminars in Hearing May 2019The purpose of this article is to provide a brief introduction and review regarding basic principles of pharmacology, including terminology and colloquialisms, as well... (Review)
Review
The purpose of this article is to provide a brief introduction and review regarding basic principles of pharmacology, including terminology and colloquialisms, as well as pharmacokinetic and pharmacodynamic principles of ototoxic agents. As an audiology practitioner, it is more important than ever to have a working knowledge regarding the known and proposed mechanisms of action for drugs and chemicals with known ototoxicity potential. Additionally, this article provides a discussion regarding the biochemistry behind distribution, which is a major step in determining ototoxic potential of known and potential ototoxins.
PubMed: 31036986
DOI: 10.1055/s-0039-1684038 -
HNO Jun 2019Modern research on ototoxicity goes back to the 1940s, when streptomycin was introduced into clinical practice. Today, aminoglycoside antibiotics and platinum-based... (Review)
Review
Modern research on ototoxicity goes back to the 1940s, when streptomycin was introduced into clinical practice. Today, aminoglycoside antibiotics and platinum-based chemotherapy, mainly cisplatin, are the most important drugs that damage the inner ear and cause hearing loss. The mode of drug administration as well as drug characteristics influence the likelihood that adequate monitoring of drug pharmacokinetics can be performed. It is not possible to predict the individual risk of treatment with an ototoxic drug, but identification of high-risk treatment protocols is important. There are many studies ongoing with the aim of discovering and developing drugs to treat different types of inner ear disorders. The mechanisms of ototoxicity and subsequent loss of hearing function have been mapped in various experimental models and have provided us with useful information for developing protective treatment. When an ototoxic lesion is established, restoration of hearing function becomes more difficult. For both aminoglycoside antibiotics and cisplatin, a large number of otoprotectors have been suggested. Systemic co-administration of an otoprotector would be the easiest approach to avoid ototoxicity in patients but it may negatively affect the intended pharmacotherapeutic aim of the ototoxic drug. New pharmacological formulations are being developed for local otoprotective treatment. This short review focuses on results from clinical reports on otoprotection in patients treated with aminoglycoside antibiotics and cisplatin. So far there is limited evidence for the safe management of otoprotection in patients. Further high-quality studies are needed to provide reliable data on the safety and effectiveness of pharmacological interventions to reduce drug-induced hearing loss.
Topics: Aminoglycosides; Anti-Bacterial Agents; Antineoplastic Agents; Cisplatin; Hearing Loss; Humans
PubMed: 30993373
DOI: 10.1007/s00106-019-0663-1 -
Neural Plasticity 2021Hearing loss is often caused by death of sensory hair cells (HCs) in the inner ear. HCs are vulnerable to some ototoxic drugs, such as aminoglycosides(AGs) and the... (Review)
Review
Hearing loss is often caused by death of sensory hair cells (HCs) in the inner ear. HCs are vulnerable to some ototoxic drugs, such as aminoglycosides(AGs) and the cisplatin.The most predominant form of drug-induced cell death is apoptosis. Many efforts have been made to protect HCs from cell death after ototoxic drug exposure. These mechanisms and potential targets of HCs protection will be discussed in this review.And we also propose further investigation in the field of HCs necrosis and regeneration, as well as future clinical utilization.
Topics: Apoptosis; Hair Cells, Auditory; Humans; Neuroprotective Agents; Ototoxicity; Oxidative Stress; Reactive Oxygen Species
PubMed: 34335732
DOI: 10.1155/2021/4909237 -
Frontiers in Neurology 2020
PubMed: 33193062
DOI: 10.3389/fneur.2020.593917