From Ototoxicity to Otoprotection: Mechanism and Protective Strategies in Cisplatin Therapy
Abstract
1. Introduction
2. Cisplatin Ototoxic Mechanisms
2.1. Absorption of Cisplatin at Cochlear Level
2.2. Cochlear ROS Generation System and Antioxidant Defenses
2.3. Mechanisms of Cisplatin-Induced Ototoxicity at the Mitochondrial Level
2.3.1. Mitochondrial Genomic Damage and the Associated Generation of ROS
2.3.2. Bcl-2 Family
2.3.3. Caspases
2.3.4. P53
2.4. Cisplatin Impact on Cellular DNA
2.5. Role of Cytokines in the Ototoxicity Process
3. Otoprotective Strategies
4. Cisplatin-Induced Ototoxicity Monitoring
5. Limitations, Conclusions, and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
A1AR | Adenosine A1 receptors |
ABR | Auditory brainstem response |
AOE | Antioxidant enzyme |
CAT | Catalase |
CB2 | Cannabinoid receptors 2 |
CTR1 | Copper transporter 1 |
CNS | Central nervous system |
CMV | Cytomegalovirus |
D-Met | D-Methionine |
DPOAE | Otoacoustic emissions and distortion product otoacoustic emissions |
EGCG | Epigallocatechin-3-gallate |
FDA | Food and Drug Administration |
GSH | Antioxidant reduced glutathione |
GSH-Px | Glutathione peroxidase |
GSSG | Oxidized glutathione |
GR | Glutathione reductase |
GST | Glutathione S-transferase |
GDRs | Global DNA repair enzymes |
HFA | High-frequency audiometry |
H2O2 | Hydrogen peroxide |
IL-1 β | Interleukin-1β |
IL-18 | Interleukin-18 |
KIM-1 | Kidney injury molecule-1 |
M-CSF | Macrophage colony-stimulating factor |
NAC | N-acetyl cysteine |
NOX3 | Adenine dinucleotide phosphate oxidase 3 |
NADP+ | Nicotinamide adenine dinucleotide phosphate |
NER | Nucleotide excision repair system |
NF-kB | Nuclear factor-kB |
OCT | Organic cation transporter |
OAE | Otoacoustic emission |
P53 | Tumor antigen p53 |
PFT- α | Pifithrin-α |
PRDX1 | Peroxiredoxin-1 |
ROS | Reactive oxygen species |
SOD | Superoxide dismutase |
STAT1 | Signal transducer and activator of transcription 1 |
STAT3 | Signal transducer and activator of transcription 3 |
STS | Sodium thiosulfate |
SNP | Single-nucleotide polymorphism |
TRPV1 | Transient receptor potential vanilloid 1 |
TCRs | Transcriptionally coupled repair enzymes |
TNF-α | Tumor necrosis factor-α |
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Drug Targets | Mechanisms of Action | Bibliographical Sources | |
---|---|---|---|
RECEPTORS | Adenosine A1 receptor (A1AR) | Drugs targeting this receptor could enhance endogenous antioxidant defenses while suppressing the inflammatory NOX3/STAT1 pathway | [26,27,28,52] |
Cannabinoid 2 receptor (CB2) | Anti-apoptotic effect | [30,31,32] | |
TRANSPORTERS | Organic cation transporter 2 (OCT2) | Involved in the mechanisms that regulate the cellular uptake of cisplatin | [12,13,53] |
Copper transporter 1 (CTR1) | Plays a role in facilitating the entry of cisplatin into cells | [10,11] | |
PRO-INFLAMMATORY MARKERS | Tumor necrosis factor-α (TNF-α) | A cytokine that promotes inflammation, triggered by cisplatin | [54] |
Signal transducer and activator of transcription-1 (STAT1) | A pro-inflammatory transcription factor | [20] | |
Nuclear factor-kB (NF-kB) | A transcription factor that promotes inflammation and apoptosis | [38,55] | |
Transient receptor potential vanilloid 1 (TRPV-1) | A marker of oxidative stress and inflammation at the cochlear level, facilitating the entry of cisplatin | [19,56] | |
ANTIOXIDANT DEFENSE SYSTEM | NOX3 | Generates ROS in cochlear cells | [17] |
Superoxide dismutase (SOD) | Plays a role in converting the superoxide anion into hydrogen peroxide (H2O2) and O2 | [57] | |
Catalase (CAT) | Converting H2O2 into H2O and O2 | [57] | |
Glutathione (GSH) | Endogenous antioxidant molecule | [24] | |
Glutathione peroxidase (GSH-Px) | Catalyzes the breakdown of H2O2 into H2O and O2 by using GSH | [57] | |
Glutathione reductase (GR) | Plays a role in regenerating GSH from GSSG | [57] | |
Glutathione S-transferase (GST) | Conjugate GSH with xenobiotics | [58] | |
Kidney injury molecule-1 (KIM-1) | Oxidative stress marker in the cochlea | [59] | |
Vitamin E | Antioxidant molecule | [60] | |
MISCELLANEOUS | Signal transducer and activator of transcription 3 (STAT3) | Plays a role in cytoprotection mechanisms | [61] |
Therapeutic Agent | Mechanisms of Action | Bibliographical Sources | |
---|---|---|---|
Antioxidant and anti-inflammatory treatments | N-acetyl cysteine (NAC) | Antioxidant molecule | [62,63,64,65] |
Sodium thiosulfate (STS) | Antioxidant molecule | [6,66,67,68] | |
D -Methionine (D -Met) | Antioxidant molecule | [69,70,71,72] | |
Amifostine | Involved in capturing free radicals | [73,74,75] | |
Allopurinol | Xanthine oxidase inhibitor | [23] | |
Ebselen | It is a glutathione peroxidase mimetic | [23,76] | |
Dexamethasone | Anti-inflammatory effect | [77,78,79,80,81] | |
Etanercept | Anti-inflammatory effect | [54,82] | |
Statins | Antioxidant and anti-inflammatory effect | [83] | |
Curcumin | Antioxidant, anti-inflammatory, anti-apoptotic effect | [84] | |
Capsaicin | Antioxidant and anti-inflammatory effect | [32] | |
Apelin-13 | Antioxidant and anti-inflammatory effect | [85] | |
Aucubin | Antioxidant and anti-inflammatory effect | [86] | |
Astaxanthin | Antioxidant, anti-apoptotic effect | [87] | |
R-phenylisopropyladenosine (R-PIA) | Anti-inflammatory effect | [28] | |
Alpha-lipoic acid | Anti-apoptotic effect | [88] | |
ROSI (ACSL4 inhibitor) | Inhibition of lipid peroxide production | [89] | |
Inhalation of gaseous H2 | Inhaling 2% H2 gas has antioxidant effects | [90] | |
Avenanthramide-C (AVN-C) | Antioxidant and anti-inflammatory effect | [91] | |
Inhibitors of cellular pathway | Agmatine | Upregulates the PI3K/AKT pathway to attenuate apoptosis | [92] |
Rutin | Prevents apoptosis by activating the PI3K/AKT signaling pathway | [93] | |
Eupatilin | Intervenes in the mitochondrial apoptosis pathway | [94] | |
Puerarin | Suppresses ROS generation, modulates Bcl-2 family proteins, and influences the mitochondrial pathway of apoptosis | [95] | |
Meclofenamic Acid | Inhibition of excessive autophagy induced by cisplatin. | [96] | |
Trehalose | Provides protection against cisplatin-induced damage to cochlear hair cells through the activation of autophagy | [97] | |
YTHDF1 | Involved in the process of autophagy | [98] | |
Other novel mechanisms antagonizing Cisplatin ototoxicity | Combination of PFT-α, D-Met | Significant cell protective effect | [99] |
The conjugation of dexamethasone with nanoparticles | Enhances the distribution of the drug and boosts dexamethasone’s solubility and bioavailability | [100] | |
Mannitol | Modulating the permeability of the blood-labyrinth barrier (BLB) | [101] | |
Aspirin | Decreasing cochlear metabolic activity | [102] | |
Cool | Reducing the absorption of cisplatin in cochlear cells, the production of reactive oxygen species, and inflammatory factors | [103] | |
Salubrinal | Affects various cellular processes | [104] | |
Acetophenone | Affects various cellular processes | [105] | |
Pifithrin-α (PFT-α) | It is a p53 inhibitor | [43,44] | |
Epigallocatechin gallate (EGCG) | STAT1 inhibitor | [61] |
Benefits | Disadvantage | |
HFA (>8 kHz) |
|
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Benefits | Disadvantage | |
DPOAE |
|
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Iațentiuc, A.; Cozma, S.R.; Frăsinariu, O.E.; Miron, I.C.; Iațentiuc, I.M.; Dima-Cozma, L.C.; Olariu, R.; Postolache, A.; Buga, A.-M.L.; Stingheriu, A.; et al. From Ototoxicity to Otoprotection: Mechanism and Protective Strategies in Cisplatin Therapy. Pharmaceuticals 2025, 18, 1543. https://doi.org/10.3390/ph18101543
Iațentiuc A, Cozma SR, Frăsinariu OE, Miron IC, Iațentiuc IM, Dima-Cozma LC, Olariu R, Postolache A, Buga A-ML, Stingheriu A, et al. From Ototoxicity to Otoprotection: Mechanism and Protective Strategies in Cisplatin Therapy. Pharmaceuticals. 2025; 18(10):1543. https://doi.org/10.3390/ph18101543
Chicago/Turabian StyleIațentiuc, Andreea, Sebastian Romică Cozma, Otilia Elena Frăsinariu, Ingrith Crenguța Miron, Iustin Mihai Iațentiuc, Lucia Corina Dima-Cozma, Raluca Olariu, Anca Postolache, Ana-Maria Laura Buga, Alexandru Stingheriu, and et al. 2025. "From Ototoxicity to Otoprotection: Mechanism and Protective Strategies in Cisplatin Therapy" Pharmaceuticals 18, no. 10: 1543. https://doi.org/10.3390/ph18101543
APA StyleIațentiuc, A., Cozma, S. R., Frăsinariu, O. E., Miron, I. C., Iațentiuc, I. M., Dima-Cozma, L. C., Olariu, R., Postolache, A., Buga, A.-M. L., Stingheriu, A., Boéchat, E., & Bitere-Popa, O. R. (2025). From Ototoxicity to Otoprotection: Mechanism and Protective Strategies in Cisplatin Therapy. Pharmaceuticals, 18(10), 1543. https://doi.org/10.3390/ph18101543