Document Type : Review Article


1 School of Rehabilitation Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

2 Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran


Background: Despite the efficiency, many side effects have been reported for cisplatin, which is a well-known anti-cancer agent. Among them we can point to ototoxicity, which seriously reduces the quality of life in cisplatin-receiving patients. Since the approach of using natural ingredients in clinic has been growing in recent years, herein, we intend to gather delegated documentations of the presented scientific reports regarding various aspects of cisplatin-induced ototoxicity (CIO) focusing on some effective natural remedies.
Methods: Well-known scientific databases such as Google Scholar, Scopus, and PubMed were employed to search the target keywords. Then, to prepare the literature, the selected contents were reviewed, analyzed, and modified at several stages.
Results: Recent studies have shown that the prevalence of CIO is very high and most cisplatin-receiving patients suffer from this complication to a certain degree. Along with other underlying factors, the roles for reactive oxygen species (ROS) and apoptotic factors have been found very significant in forming the process of CIO. In order to alleviate the complication, various pharmacological and non-pharmacological treatments have been introduced and suggested. Particularly, special attention has been paid to natural products in recent decades. In this regard, many of these compounds were found efficacious and safe.
Conclusion: This review showed that, many natural products are able to attenuate CIO through various mechanisms, among which anti-oxidative and anti-apoptotic pathways would be the most important ones. Therefore, as a novel pharmacological approach, they have the potential to be focused in future mechanistic studies.



As a debilitating disorder, ototoxicity, which can be caused by being exposed to some drugs and toxins, seriously complicates the quality of life of patients. Ototoxic agents affect vestibular and cochlear organs, leading to reversible and irreversible damages. Among the ototoxic drugs, anti-malarial agents, loop diuretics, macrolide, and aminoglycoside antibiotics and some anti-cancer drugs can be mentioned. Platinum based chemotherapeutic agents are essential component of many cancer chemotherapy protocols and have been found effective in the treatment of various types of cancer including head and neck, ovarian, testicular, cervical, bladder, head and neck, and non-small cell lung cancers (1-4). Cisplatin is one of the renowned platinum based chemotherapeutic drugs that usually causes bilateral ototoxicity. At the beginning of the treatment, not only the hearing loss usually occurs corresponding to high frequencies but also hearing the lower frequencies might also be affected (5-8). Although the severity of the damage would depend on the administered dose, it is a very common side effect and about 93% of the patients treated with this drug report some degree of irreversible hearing loss (3, 9-11). Many research studies have been carried out to justify the high prevalence of this complication, as a result, various mechanisms have been proposed in this domain (12-15). It is believed that the severity of ototoxicity in cisplatin-treated patients varies from case to case and these patients customarily may suffer from otalgia and tinnitus (which are defined as ear pain and the perception of noise in ears, respectively) or some degrees of hearing loss. It is important to note that, genetic polymorphisms can underlie the severity and prevalence of these variations (16). In recent years, numerous studies have been conducted in order to attenuate cisplatin-induced ototoxicity (CIO) (17-20). Among them, the use of herbal products have always received a substantial attention from the scholars (21, 22). Regarding natural products as a valued reservoir of novel medicines and complementary products, they keep on representing a challenge to science in consequence of phytochemical diversities bringing about varied biological effects. Subsequently, the aim of this study was to review the various aspects of CIO focusing on the important natural remedies.


Referenced articles (published over the last three decades) were selected by searching through well-known scientific databases such as Google Scholar, Scopus, and PubMed. The terms, “Cancer”, “Chemotherapy”, “Cisplatin”, “Ototoxicity” and “Natural products” were used as the keywords. Selected contents were reviewed at several stages before writing the literature and the final manuscript was approved by all the authors.


Prevalence of CIO

Several risk factors can exacerbate the severity of CIO including anemia, renal failure, and head and neck irradiation or hypoalbuminemia. As can be deduced from the studies, underage and elderly patients are more exposed to the risk (1). In this regard, the prevalence of severe hearing loss among cisplatin-treated patients has been reported 40%–80% for adults and 90% for pediatrics (23). Besides, the gender of the patients is the other variable, which is debatable in this scope as males are more susceptible than females to develop the condition (24). On the other hand, several genetic factors influence the severity of CIO. Seeing that some genotypes are not able to metabolize and detoxify cisplatin, therefore, the patients would be more exposed to the risk (25). Furthermore, the duration of the therapy and the administered dose together with the nutritional status of the patients would directly affect the severity of the mentioned complication (6). More to the point, considering the increasing rate of cancer in developing countries, the use of chemotherapy drugs and prevalence of their side effects would be higher in these countries(26). Taken as a whole, the high incidence of cancer and the growing use of chemotherapy drugs, on one hand, and the high prevalence of ototoxicity in patients receiving cisplatin, on the other hand, would justify the burgeoning bulk of studies in this area.

Molecular Mechanisms

In recent years, researchers have established valuable findings regarding the mechanisms involved in the development of CIO. Many of these outcomes support the undeniable role of reactive oxygen species (ROS) in this process. In view of the fact that the body’s antioxidant capacity is limited, cisplatin induced over-production of free radicals brings about oxidative stress leading to harmful effects. The involvement of signal transducers and activators of transcription (STATs), NF-κB protein complex, NADPH oxidases such as NOX3 and high mobility group (HMG) proteins have also been reported (5, 25, 27). These mechanisms may finally result in damages in neurons of the spiral ganglion, the hair cells in the organ of Corti, and the epithelial cells of the stria vascularis (25). Likewise, alkylation‐like reactions would play an important role in the mentioned processes. It would be a mechanism by which cisplatin damages the nuclear DNA. High mobility group proteins are a type of protein that are able to inhibit transcription factors following binding to DNA. The result could also be starting the apoptosis process (6). The involvement of BCL2-associated X (BAX) proteins has also been demonstrated in these processes. Research evidence indicate increased levels of BAX and decreased levels of BCL2 (an anti-apoptotic protein) proteins following cisplatin administration (28). The mentioned mechanisms would lead to dysfunctions in cochlear outer cells and then gradually may affect other regions (29). So, it can be concluded that ROS production, the involvement of signal transducers and activators of transcription (STATs), NF-κB protein complex, NADPH oxidases such as NOX3 and high mobility group (HMG) proteins, alkylation‐like reactions, and imbalances between apoptotic and anti-apoptotic factors may be the leading underlying causes for CIO. However, the exact molecular pathways are still unclear.

Natural Pharmaceutical Approaches

Not surprisingly, the widespread usage of natural products available among the populace for treating different sorts of disorders regardless of their effectiveness and safety especially between people with low literacy, makes it ever more essential to acquire the necessary evidence-based information around the natural remedies for developing more efficient, safe, and reliable natural treatments. In the past couple of decades, the approach to the use of natural resources for producing pharmaceutical compounds has received considerable attention. Natural remedies are mainly originated and produced from different kinds of medicinal plants, certain types of animals or of microorganisms (30-36). In this manuscript, we aimed to list some important natural compounds in the literature that have been found effective in preventing or improving CIO.

Peanut Sprout

Peanut sprout, which is known to be rich in various valuable nutrients, had been the subject of numerous studies reporting about its useful pharmacological effects. Its anti-cancer, anti-inflammatory, and anti-aging effects, on one hand, and its antioxidant capacity, on the other hand, have caught researchers’ attention to this natural product (37-41). Among its valuable pharmacological abilities, its attenuating effect on CIO can be mentioned. In a study conducted by Youn et al. it was revealed that peanut sprout would be able to stimulate the Akt/Nrf-2 pathway in the auditory cells. They declared that the observed stimulation would justify its antioxidant and consequently otoprotective effects (41).


Paeonia lactiflora, which is a well-known medicinal plant, grows in different regions of the world. In many countries, its various applications in traditional medicine have been reported before (42). Biological activities of this plant would be due to its different bioactive compounds (9, 42). Paeoniflorin, a monoterpene glycoside, is one of the key bioactive compounds whose neuroprotective potential as well as its anti‐apoptotic, anti-oxidative, and anti-inflammatory effects have been investigated and reported in previous studies (43, 44). In a recent study in 2019, the attenuating effect of paeoniflorin on CIO was evaluated. The results of the study indicated that paeoniflorin would be able to improve CIO via decreasing the production of ROS, increasing PINK1 expression, reducing the accumulation of BAD proteins on mitochondria, and consequently diminishing the cisplatin-induced mitochondrial apoptosis in spiral ganglion neurons (9).


It has already been substantiated that honey and propolis are two rich sources of chrysin (45). This natural flavone has attracted the attention of many researchers in recent years due to its various pharmacological properties. Anti-allergic, antioxidant, and anti-inflammatory effects are the only small part of this compound’s medicinal properties. Besides, otoprotective effect of chrysin have also been evaluated and it has been shown that it would be effective in preventing CIO (45, 46).


For centuries, Astragalus membranaceus has been holding a special place in traditional medicine of different countries. After China, its medicinal usage has also become popular in other countries such as the US and Japan (47). Many of its pharmacological effects, such as the antioxidant properties, are due to the activity of a class of phytochemicals namely astragalosides (48). It has been reported that the attenuating effect of this plant on CIO was due to the antioxidant capacity of its astragalosides (49).


Grapes and peanuts are two sources of the natural polyphenol, resveratrol (50). Cardioprotective, cancer preventive and estrogen receptor modulatory effects of resveratrol as well as its other pharmacological effects have been reported in the pertinent literature in this domain (51). Over the past decade, there have been several studies available online about the protective effect of resveratrol against CIO. These studies have suggested the antioxidant capacity of resveratrol as the mechanism underlying its otoprotective property (21, 52-54).

Korean Red Ginseng

People in East Asia have found Korean ginseng (Panax ginseng), an effective medicinal plant for centuries. Japan, Korea, and China are some of the countries where the herb has been widely used regarding different medical purposes such as the treatment of cardiovascular diseases, cancers, and diabetes (55, 56). The effect of Korean red ginseng (the steamed root of the plant) on CIO has also been assessed in several studies. It was stated that the anti-apoptotic, anti-oxidative, and anti-inflammatory effects of the plant would play a significant role in its protective effects against the ototoxicity (57-59).


In physiological conditions, the pineal gland is responsible for the secretion of melatonin. In addition to regulating the circadian cycle, melatonin seems to be involved in maintaining immune function (60). The efficacy of melatonin in attenuating CIO has also been evaluated. All the studies confirm the protective role of melatonin against CIO. Although other mechanisms such as dopaminergic modulation have been reported for actions of melatonin, the main mechanism for its otoprotective effects, seems to be through antioxidative pathways (61-64).

Vitamin E

As a well-known antioxidant, vitamin E has always been a focual point for researchers to find its various beneficial therapeutic effects. It is a lipid soluble compound and the RRR-α-tocopherol is the most common form of this vitamin in natural resources. Numerous therapeutic effects have been attributed to vitamin E to date. Abilities in attenuating the oxidative stress in hemodialysis patients, improving the condition of myocardial infarction patients, and enhancing the bone histomorphometry parameters have been reported for vitamin E as well as the other significant beneficial effects (65-70). Apart from these therapeutic effects, vitamin E treatment has been shown to improve CIO. In recent studies, the antioxidant activity, neuroprotecting and inhibiting lipid peroxidation, and DNA fragmentation within the cochlea have been noted as the underlying protective mechanisms against CIO (71-75).


The medicinal use of curcumin, a famous phytochemical which is extracted from Curcuma longa, has been of particular interest to researchers for years. It seems to be beneficial in various diseases such as arthritis, diabetes, and Alzheimer's disease (76). In addition to these applications, the mitigating effect of curcumin on CIO has also been proven. It is reported that curcumin would attenuate the mentioned toxicity via increasing Heme Oxygenase-1 gene expression and Nrf-2 translocation, as well as antioxidant and anti-inflammatory activity (74, 76-79).


Tomatoes are natural sources of a carotenoid, which is called lycopene. In addition to its antioxidant property, lycopene has been known for its cognitive enhancing, neuroprotective, and anti-inflammatory properties (80, 81). Moreover, some useful therapeutic effects on CIO have been reported in which the inhibitory effects on oxidative process, inflammatory, and apoptotic pathways have been declared to be among the involved protective mechanisms (82-84).

Caffeic Acid

Caffeic acid phenethyl ester (CAPE) is another useful natural compound, which is found in some natural resources. CAPE is famous for its antioxidant, anti-inflammatory, and immunomodulatory capacity, which are the underlying mechanisms for various therapeutic effects (85). Among them the beneficial effects on vascular and reperfusion injuries have already been reported. On the other hand, its effectiveness on reducing CIO have been shown in previous studies. Although studies have suggested that all the mentioned mechanisms may underlie the protective effects of caffeic acid against CIO, more emphasis has been placed on its antioxidant activity as the responsible protective pathway (85-89).


The main goal of this article was to review a collection of natural compounds that would help cisplatin receiving patients cope better with ototoxicity, the well-known side effect of the drug. Some of the compounds such as melatonin, curcumin, and vitamin E have attracted more attention in recent studies. As discussed, among the mechanisms through which these compounds act, antioxidant, anti-inflammatory and anti-apoptotic pathways may be the most important ones (Table). Each of these pathways can be a target for future studies and therefore a key to find better treatments for cisplatin-induced ototoxicity.


The authors would like to appreciate the Faculty of Pharmacy (Tabriz University of Medical Sciences) for the facilities provided for writing this review.


None to be declared.








    1. Rybak L, Ramkumar V. Ototoxicity. Kidney Int 2007;72:931-5.
    2. Reavis KM, McMillan G, Austin D, Gallun F, Fausti SA, Gordon JS, et al. Distortion-product otoacoustic emission test performance for ototoxicity monitoring. Ear Hear 2011;32:61-74.
    3. Kilic K, Sakat MS, Akdemir FNE, Yildirim S, Saglam YS, Askin S. Protective effect of gallic acid against cisplatin-induced ototoxicity in rats. Braz J Otorhinolaryngol 2019;85:267-74.
    4. Eroğlu O, Karlıdağ T, Kuloğlu T, Keleş E, Kaygusuz İ, Yalçın Ş. The Protective Effect of Cortexin on Cisplatin-Induced Ototoxicity. J Int Adv Otol 2018;14:27-33.
    5. Ding Dl, Ping W, Haiyan J, Coling D, Salvi R. Gene expression in cisplatin ototoxicity and protection with p53 inhibitor. J Otol 2009;4:61-70.
    6. Schacht J, Talaska AE, Rybak LP. Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention. Anat Rec 2012;295:1837-50.
    7. Brungart D, Schurman J, Konrad-Martin D, Watts K, Buckey J, Clavier O, et al. Using tablet-based technology to deliver time-efficient ototoxicity monitoring. Int J Audiol 2018;57:S78-S86.
    8. Rolland V, Meyer F, Guitton MJ, Bussières R, Philippon D, Bairati I, et al. A randomized controlled trial to test the efficacy of trans-tympanic injections of a sodium thiosulfate gel to prevent cisplatin-induced ototoxicity in patients with head and neck cancer. Otolaryngol Head Neck Surg 2019;48:4.
    9. Yu X, Man R, Li Y, Yang Q, Li H, Yang H, et al. Paeoniflorin protects spiral ganglion neurons from cisplatin‐induced ototoxicity: Possible relation to PINK1/BAD pathway. JCMM 2019;23:5098-107.
    10. Chirtes F, Albu S. Prevention and restoration of hearing loss associated with the use of cisplatin. Biomed Res Int 2014;2014:925485.
    11. Sakat MS, Kilic K, Akdemir FNE, Yildirim S, Eser G, Kiziltunc A. The effectiveness of eugenol against cisplatin-induced ototoxicity. Braz J Otorhinolaryngol 2019;85:766-73.
    12. Sheth S, Sheehan K, Dhukhwa A, Al Aameri RF, Mamillapalli C, Mukherjea D, et al. Oral Administration of Caffeine Exacerbates Cisplatin-Induced Hearing Loss. Sci Rep 2019;9:9571.
    13. Bielefeld EC, Henderson D. Mechanisms of cisplatin ototoxicity and routes for intervention. Perspect ASHA Spec Interest Groups 2011;15:338.
    14. Gonçalves M, Silveira A, Teixeira A, Hyppolito M. Mechanisms of cisplatin ototoxicity: theoretical review. J Laryngol Otol 2013;127:536-41.
    15. Ravi R, Somani SM, Rybak LP. Mechanism of cisplatin ototoxicity: antioxidant system. Pharmacol Toxicol 1995;76:386-94.
    16. Mukherjea D, Rybak LP. Pharmacogenomics of cisplatin-induced ototoxicity. Pharmacogenomics 2011;12:1039-50.
    17. Taş BM, Şimşek G, Azman M, Kılıç R. Efficacy of 2 Different Intratympanic Steroid Regimen on Prevention of Cisplatin Ototoxicity: An Experimental Study. Ear Nose Throat J 2019:0145561319874311.
    18. R Popay A, R Lloyd D, N Wass M, Michaelis M. Dexamethasone for the Prevention of Cisplatin-induced Ototoxicity. Clin Cancer Drugs 2017;4:59-64.
    19. Sarafraz Z, Ahmadi A, Daneshi A. Transtympanic injections of N-acetylcysteine and dexamethasone for prevention of cisplatin-induced ototoxicity: double blind randomized clinical trial. Int Tinnitus J 2018;22:40-5.
    20. Aslıer NGY, Tağaç AA, Durankaya SM, Çalışır M, Ersoy N, Kırkım G, et al. Dexamethasone-loaded chitosan-based genipin-cross-linked hydrogel for prevention of cisplatin induced ototoxicity in Guinea pig model. Int J Pediatr Otorhinolaryngol 2019;122:60-9.
    21. Erdem T, Bayindir T, Filiz A, Iraz M, Selimoglu E. The effect of resveratrol on the prevention of cisplatin ototoxicity. Eur Arch Oto-Rhino-L 2012;269:2185-8.
    22. Huang X, Whitworth CA, Rybak LP. Ginkgo biloba extract (EGb 761) protects against cisplatin-induced ototoxicity in rats. Otol Neurotol 2007;28:828-33.
    23. Wang X, Chen Y, Tao Y, Gao Y, Yu D, Wu H. A666-conjugated nanoparticles target prestin of outer hair cells preventing cisplatin-induced hearing loss. Int J Nanomedicine 2018;13:7517-31.
    24. Lui G, Bouazza N, Denoyelle F, Moine M, Brugières L, Chastagner P, et al. Association between genetic polymorphisms and platinum-induced ototoxicity in children. Oncotarget 2018;9:30883-93.
    25. Tropitzsch A, Arnold H, Bassiouni M, Müller A, Eckhard A, Müller M, et al. Assessing cisplatin-induced ototoxicity and otoprotection in whole organ culture of the mouse inner ear in simulated microgravity. Toxicol Lett 2014;227:203-12.
    26. Paken J, Govender CD, Pillay M, Sewram V. Cisplatin-associated ototoxicity: a review for the health professional. J Toxicol 2016;2016:1809394.
    27. Rybak LP. Mechanisms of cisplatin ototoxicity and progress in otoprotection. Curr Opin Otolaryngol Head Neck Surg 2007;15:364-9.
    28. Fujimoto C, Yamasoba T. Mitochondria-targeted antioxidants for treatment of hearing loss: a systematic review. Antioxidants 2019;8:109.
    29. Ding D, Jiang H, Zhang J, Xu X, Qi W, Shi H, et al. Cisplatin-induced vestibular hair cell lesion-less damage at high doses. J Otol 2018;13:115-21.
    30. Von Nussbaum F, Brands M, Hinzen B, Weigand S, Häbich D. Antibacterial natural products in medicinal chemistry—exodus or revival? Angew Chem Int Ed 2006;45:5072-129.
    31. Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007;70:461-77.
    32. Baker DD, Chu M, Oza U, Rajgarhia V. The value of natural products to future pharmaceutical discovery. Nat Prod Rep 2007;24:1225-44.
    33. Habibi asl B, Majidi Z, Fekri K, Delazar A, Vaez H. Evaluation of the Effect of Aerial Parts of Scrophularia atropatana Grossh Total Extracts on Analgesic Activity and Morphine Induced Tolerance in Mice. Pharm Sci 2018;24:112-7.
    34. Farajdokht F, Vatandoust SM, Hosseini L, Fekri K, Aghsan SR, Majdi A, et al. Sericin Protects Against Acute Sleep Deprivation-Induced Memory Impairment via Enhancement of Hippocampal Synaptic Protein Levels and Inhibition of Oxidative Stress and Neuroinflammation in Mice. Brain Res Bull 2021.
    35. Habibi-Asl B, Parvizpur A, Fekri K, Jahanpanah H, Rezaei H, Charkhpour M. Effects of sodium selenite and vitamin E on the development of morphine dependency in mice. Pharm Sci 2020.
    36. Mohajjel Nayebi A, Hashemian A, Rezazadeh H, Charkhpour M, Fekri K, Haddadi R. Silymarin reduced cisplatin-induced hyperalgesia by suppressing oxidative stress in male rats. Physiol Pharmacol 2021;25.
    37. Choi JY, Choi DI, Lee JB, Yun SJ, Lee DH, Eun JB, et al. Ethanol extract of peanut sprout induces Nrf2 activation and expression of antioxidant and detoxifying enzymes in human dermal fibroblasts: Implication for its protection against UVB‐irradiated oxidative stress. Photochem Photobiol 2013;89:453-60.
    38. Kang H-I, Kim J-Y, Kwon S-J, Park K-W, Kang J-S, Seo K-I. Antioxidative effects of peanut sprout extracts. Korean J Food & Nutr 2010;39:941-6.
    39. Ha AW, Kim WK, Kim JH, Kang NE. The supplementation effects of peanut sprout on reduction of abdominal fat and health indices in overweight and obese women. Nutr Res Pract 2015;9:249-55.
    40. Wang K-H, Lai Y-H, Chang J-C, Ko T-F, Shyu S-L, Chiou RY-Y. Germination of peanut kernels to enhance resveratrol biosynthesis and prepare sprouts as a functional vegetable. J Agric Food Chem 2005;53:242-6.
    41. Youn CK, Jo E-R, Sim J-H, Cho SI. Peanut sprout extract attenuates cisplatin-induced ototoxicity by induction of the Akt/Nrf2-mediated redox pathway. Int J Pediatr Otorhinolaryngol 2017;92:61-6.
    42. Braca A, Van Kiem P, Yen PH, Nhiem NX, Quang TH, Cuong NX, et al. New monoterpene glycosides from Paeonia lactiflora. Fitoterapia 2008;79:117-20.
    43. Tao Y, Wen Z, Song Y, Wang H. Paeoniflorin attenuates hepatic ischemia/reperfusion injury via anti-oxidative, anti-inflammatory and anti-apoptotic pathways. Exp Ther Med 2016;11:263-8.
    44. Wang D, Wong HK, Feng Y-B, Zhang Z-J. Paeoniflorin, a natural neuroprotective agent, modulates multiple anti-apoptotic and pro-apoptotic pathways in differentiated PC12 cells. Cell Mol Neurobiol 2013;33:521-9.
    45. Kasala ER, Bodduluru LN, Madana RM, Gogoi R, Barua CC. Chemopreventive and therapeutic potential of chrysin in cancer: mechanistic perspectives. Toxicol Lett 2015;233:214-25.
    46. Kelles M, Tan M, Kalcioglu MT, Toplu Y, Bulam N. The protective effect of Chrysin against cisplatin induced ototoxicity in rats. Indian J Otolaryngol Head Neck Surg 2014;66:369-74.
    47. Zhao K, Mancini C, Doria G. Enhancement of the immune response in mice by Astragalus membranaceus extracts. Immunopharmacology 1990;20:225-33.
    48. Yin Y-Y, Li W-P, Gong H-L, Zhu F-F, Li W-Z, Wu G-C. Protective effect of astragaloside on focal cerebral ischemia/reperfusion injury in rats. Am J Chin Med 2010;38:517-27.
    49. Xiong M, He Q, Wang J, Lai H. Astragalosides reduce cisplatin ototoxicity in guinea pigs. ORL 2011;73:131-6.
    50. Bradamante S, Barenghi L, Villa A. Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev 2004;22:169-88.
    51. Bhat KP, Kosmeder JW, Pezzuto JM. Biological effects of resveratrol. Antioxid Redox Signal 2001;3:1041-64.
    52. Yumusakhuylu AC, Yazici M, Sari M, Binnetoglu A, Kosemihal E, Akdas F, et al. Protective role of resveratrol against cisplatin induced ototoxicity in guinea pigs. Int J Pediatr Otorhinolaryngol 2012;76:404-8.
    53. Şimşek G, Tokgoz SA, Vuralkan E, Caliskan M, Besalti O, Akin I. Protective effects of resveratrol on cisplatin-dependent inner-ear damage in rats. Eur Arch Oto-Rhino-L 2013;270:1789-93.
    54. Lee SH, Kim HS, An YS, Chang J, Choi J, Im GJ. Protective effect of resveratrol against cisplatin-induced ototoxicity in HEI-OC1 auditory cells. Int J Pediatr Otorhinolaryngol 2015;79:58-62.
    55. Kwak Y-S, Kyung J-S, Kim JS, Cho JY, Rhee M-H. Anti-hyperlipidemic effects of red ginseng acidic polysaccharide from Korean red ginseng. Biol Pharm Bull 2010;33:468-72.
    56. Lee SM, Bae B-S, Park H-W, Ahn N-G, Cho B-G, Cho Y-L, et al. Characterization of Korean Red Ginseng (Panax ginseng Meyer): history, preparation method, and chemical composition. J Ginseng Res 2015;39:384-91.
    57. Im GJ, Chang JW, Choi J, Chae SW, Ko EJ, Jung HH. Protective effect of Korean red ginseng extract on cisplatin ototoxicity in HEI‐OC1 auditory cells. Phytother Res 2010;24:614-21.
    58. Olgun Y, Kırkım G, Altun Z, Aktaş S, Kolatan E, Kiray M, et al. Protective effect of Korean red ginseng on cisplatin ototoxicity: is it effective enough? J Int Adv Otol 2016;12:177-83.
    59. Kim SJ, Kwak HJ, Kim DS, Choi HM, Sim JE, Kim SH, et al. Protective mechanism of Korean Red Ginseng in cisplatin-induced ototoxicity through attenuation of nuclear factor-κB and caspase-1 activation. Mol Med Rep 2015;12:315-22.
    60. Biancatelli RMLC, Berrill M, Mohammed YH, Marik PE. Melatonin for the treatment of sepsis: the scientific rationale. J Thorac Dis 2020;12:S54–S65.
    61. Lopez‐Gonzalez MA, Guerrero JM, Rojas F, Delgado F. Ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants. J Pineal Res 2000;28:73-80.
    62. Demir MG, Altıntoprak N, Aydın S, Kösemihal E, Başak K. Effect of Transtympanic Injection of Melatonin on Cisplatin-Induced Ototoxicity. J Int Adv Otol 2015;11:202-6.
    63. Reiter R, Tan D, Korkmaz A, Fuentes-Broto L. Drug-mediated ototoxicity and tinnitus: alleviation with melatonin. J Physiol Pharmacol 2011;62:151-7.
    64. Gusmão de Araujo J, Sampaio ALL, Ramos Venosa A, Oliveira CACPd. The potential use of melatonin for preventing cisplatin ototoxicity: an insight for a clinical approach. Adv Otolaryngol 2014;2014:185617.
    65. Steiner M. Vitamin E: more than an antioxidant. Clin Cardiol 1993;16:16-8.
    66. Herrera E, Barbas C. Vitamin E: action, metabolism and perspectives. J Physiol Biochem 2001;57:43-56.
    67. Cristol J, Bosc J, Badiou S, Leblanc M, Lorrho R, Descomps B, et al. Erythropoietin and oxidative stress in haemodialysis: beneficial effects of vitamin E supplementation. Nephrol Dial Transplant 1997;12:2312-7.
    68. Sethi R, Takeda N, Nagano M, Dhalla NS. Beneficial effects of vitamin E treatment in acute myocardial infarction. J Cardiovasc Pharmacol Ther 2000;5:51-8.
    69. Mehat MZ, Shuid AN, Mohamed N, Muhammad N, Soelaiman IN. Beneficial effects of vitamin E isomer supplementation on static and dynamic bone histomorphometry parameters in normal male rats. J Bone Miner Metab 2010;28:503-9.
    70. Niki E. Evidence for beneficial effects of vitamin E. Korean J Intern Med 2015;30:571-9.
    71. Kalkanis JG, Whitworth C, Rybak LP. Vitamin E reduces cisplatin ototoxicity. Laryngoscope 2004;114:538-42.
    72. Paksoy M, Ayduran E, Şanlı A, Eken M, Aydın S, Oktay ZA. The protective effects of intratympanic dexamethasone and vitamin E on cisplatin-induced ototoxicity are demonstrated in rats. Med Oncol 2011;28:615-21.
    73. Villani V, Zucchella C, Cristalli G, Galiè E, Bianco F, Giannarelli D, et al. Vitamin E neuroprotection against cisplatin ototoxicity: Preliminary results from a randomized, placebo‐controlled trial. Head Neck 2016;38:E2118-E21.
    74. Soyalıç H, Gevrek F, Koç S, Avcu M, Metin M, Aladağ İ. Intraperitoneal curcumin and vitamin E combination for the treatment of cisplatin-induced ototoxicity in rats. Int J Pediatr Otorhinolaryngol 2016;89:173-8.
    75. Pace A, Carpano S, Galie E, Savarese A, Della Giulia M, Aschelter A, et al. Vitamin E in the neuroprotection of cisplatin induced peripheral neurotoxicity and ototoxicity. J Clin Oncol 2007;25:9114.
    76. Fetoni AR, Eramo SL, Paciello F, Rolesi R, Podda MV, Troiani D, et al. Curcuma longa (curcumin) decreases in vivo cisplatin-induced ototoxicity through heme oxygenase-1 induction. Otol Neurotol 2014;35:e169-e77.
    77. Salehi P, Akinpelu OV, Waissbluth S, Peleva E, Meehan B, Rak J, et al. Attenuation of cisplatin ototoxicity by otoprotective effects of nanoencapsulated curcumin and dexamethasone in a guinea pig model. Otol Neurotol 2014;35:1131-9.
    78. Fetoni AR, Paciello F, Mezzogori D, Rolesi R, Eramo SLM, Paludetti G, et al. Molecular targets for anticancer redox chemotherapy and cisplatin-induced ototoxicity: the role of curcumin on pSTAT3 and Nrf-2 signalling. Br J Cancer 2015;113:1434-44.
    79. Paciello F, Fetoni AR, Mezzogori D, Rolesi R, Di Pino A, Paludetti G, et al. The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity. Sci Rep 2020;10:1063.
    80. Elango P, Asmathulla S. A Systematic Review on Lycopene and its Beneficial Effects”. Biomed Pharmacol J 2017;10:2113-20.
    81. Story EN, Kopec RE, Schwartz SJ, Harris GK. An update on the health effects of tomato lycopene. Annu Rev Food Sci Technol 2010;1:189-210.
    82. Özkırış M, Kapusuz Z, Karaçavuş S, Saydam L. The effects of lycopene on cisplatin-induced ototoxicity. Eur Arch Oto-Rhino-L 2013;270:3027-33.
    83. Esen E, Özdoğan F, Gürgen SG, Özel HE, Başer S, Genç S, et al. Ginkgo biloba and lycopene are effective on cisplatin induced ototoxicity? J Int Adv Otol 2018;14:22-6.
    84. Cicek MT, KALCİOĞLU MT, Bayindir T, Toplu Y, Iraz M. The effect of lycopene on the ototoxicity induced by cisplatin. Turk J Med Sci 2014;44:582-5.
    85. Tolba MF, Omar HA, Azab SS, Khalifa AE, Abdel-Naim AB, Abdel-Rahman SZ. Caffeic acid phenethyl ester: a review of its antioxidant activity, protective effects against ischemia-reperfusion injury and drug adverse reactions. Crit Rev Food Sci Nutr 2016;56:2183-90.
    86. Aydogan H, Gurlek A, Parlakpinar H, Askar I, Bay-Karabulut A, Aydogan N, et al. Beneficial effects of caffeic acid phenethyl ester (CAPE) on the ischaemia-reperfusion injury in rat skin flaps. J Plast Reconstr Aesthet Surg 2007;60:563-8.
    87. Maffia P, Ianaro A, Pisano B, Borrelli F, Capasso F, Pinto A, et al. Beneficial effects of caffeic acid phenethyl ester in a rat model of vascular injury. Br J Pharmacol 2002;136:353-60.
    88. Ozbay M, Sengul E, Kinis V, Alabalik U, Yilmaz B, Topcu I. Effects of caffeic acid phenethyl ester on cisplatin ototoxicity. B-ENT 2016;12:211-8.
    89. Kizilay A, Kalcioglu M, Ozerol E, Iraz M, Gulec M, Akyol O, et al. Caffeic acid phenethyl ester ameliorated ototoxicity induced by cisplatin in rats. J Chemother 2004;16:381-7.