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The Effect of Otoprotective Substances Against Cisplatin Exposure: A Literature Review

Introduction: Progressive and irreversible hearing loss is the most frequent side effect in patients using platinum therapy for head and neck malignancies. Previous studies on cisplatin-induced ototoxicity have shown that accumulation of reactive oxygen species leads to oxidative stress and subsequent intracellular reactions, eventually leading to cell-death. The aim of this study is to review recent evidence about the use of different substances and their otoprotective effect in humans or animals exposed to cisplatin therapy. Methods: Scientific databases such as PubMed and Cochrane were thoroughly searched from 14/04/20 to 02/05/20, based on the next keywords: cisplatin ototoxicity, cisplatin audition side effects, platinum induced ototoxicity, reduction of cisplatin ototoxicity, otoprotection against cisplatin. We include clinical trials, randomized controlled trials, reviews and systematic reviews published in English over the last five years. Results and Discussion: Many substances have been used to experience their protective use in cisplatin exposure, but the minority have shown a positive effect in humans such as sodium thiosulfate and N-acetylcysteine, some others are in the experimental phase in animals or in in-vivo phase and others have not shown favorable results at all. Conclusion: Cisplatin has been reported to be a substance that can cause an important otoacoustic damage, but it is essential in the treatment of different types of cancer, so the benefit is worth the risk, but in order to avoid the ototoxic damage, otoprotective substances should be prescribed before and during the administration of cisplatin.

for head and neck malignancies. Otalgia, tinnitus and vestibular alterations are other common side effects found [2]. The prevalence of ototoxicity due to platinum analogues treatment ranges from 4% to 90% [3,4].
Recent research report that pediatric patients who undergo platinum analogues chemotherapy have cognitive and emotional development retardment. There is no treatment protocol established for patients with hearing loss due to platinum therapy and no prevention measures are defined for patients who require chemotherapy [5].
Survival rates of head and neck malignancies for pediatric and adult patients average 80% for some types of cancer treated with cisplatin, with irreversible hearing loss rates during treatment as high as 95%. [1,6]. Currently, in the US there are 14.5 to 15.5 million of cancer treatment survivors, which they are expected to increase to 10 million in 2026 due to recent advances in early cancer detection and treatment, so a special focus is needed not only in the cure but in the quality of life care of people treated with chemotherapy [2,7].

Background
Cisplatin is a well-known anticancer drug. The substance primarily causes cell death by intercalating DNA, leading to a major antineoplastic effect. However, the risk of ototoxic and nephrotoxic side effects commonly hinders the use of higher doses that could otherwise maximize its antineoplastic effects [8]. Clinically, cisplatin induced ototoxicity appears generally as a progressive, bilateral and irreversible sensorineural hearing loss at high frequencies and progresses towards the lower frequencies [9].

Cochlea-Physiology
The cochlea has high requirements of energy due to its increased metabolic activity. During mitochondrial ATP production process an electron leakage can occur reacting with oxygen to produce free radicals which in normal conditions are buffered by antioxidant cellular mediators. External situations such as platinum analogues therapy, could stimulate oxidative stress accelerating enzymes or inactivate antioxidant processes resulting in cochlear injury [10]. In normal conditions the cochlea has an efficient antioxidant defense system based on vitamins C and E and low molecular weight thiols, like glutathione. However, with increasing metabolic stress due to inherent pathologies additional antioxidant supplementation may be needed [11].

Ototoxicity-Theory
Cisplatin has a preference over three principal structures in the cochlea: Corti's organ, spiral ganglionar cells (SGC) and lateral wall (stria vascularis) [1]. Cisplatin is absorbed by the cochlear cells and stria vascularis by the Organic Cation Transporter (OCT-2) and the Copper Transport Protein (CTR1) present in the cellular wall resulting in increasing cochlear cells cisplatin levels [3].
Previous studies on cisplatin-induced ototoxicity have shown that accumulation of reactive oxygen species (ROS) leads to oxidative stress and subsequent intracellular reactions, eventually leading to cell-death [8]. Excessive ROS can induce apoptosis through extrinsic and intrinsic pathways. Cellular stress, such DNA damage, results in the release of cytochrome-c from the mitochondria causing activation of procaspase-9 through the interaction with apoptosis promoting activation of factor-1 and formation of an active apoptosome complex [9]. Patient susceptibility is given by certain genes that may be related to other pathologies such as sensorineural sudden hearing loss and mitochondrial dysfunction [7,12,13].

Otoprotectors
The following groups of drugs have been recently studied because of the interaction and protection role they have in the different processes of cochlear cell damage.

Corticosteroids
Dexamethasone is reported as an effective treatment alternative and clinical improvement measure against sensorineural sudden hearing loss, Meniere's disease or Bell's palsy. Blockage of inflammation mediators and cellular death may be the underlying mechanism by which steroids show clinical improvement in patients using cisplatin, so different dosage and compounds are being studied to facilitate absorption and administration [14]. Additionally, the cisplatin/DEX-SILK group presented longer drug exposure with desirable levels 160 hours after administration and detectable levels 20 days after [15].

A666-DEX-NP:
The A666 nanoparticle in combination with dexamethasone increases the aforementioned specific affinity for lateral wall cells, proven in vivo and in vitro models. In vitro models showed increased protection significance over cell vitality (p<0.05) and better low frequency response evaluated by ABR [16]. OTO-104 was also effective against chronic cisplatin administration, but the otoprotective effect depended on dexamethasone nuclear receptor pathways. A single dose of dexamethasone or lower doses of OTO-104 were not effective [17]. In Hei-OCI cells ALA reduces cisplatin-induced apoptotic cell death, increasing significantly 87% cell viability in those pretreated with 2 mM ALA. Post-treatment also showed 78% cell viability with 1 mM. ALA also reduces ROS levels in HEI-OCI cells, demonstrated by fluorescence intensity with 2´, 7´-dichlorofluorescein diacetate [19]. demethylase that contributes to epigenetic RNA modification.

Organic compounds
Its dysregulation is related to obesity, brain development and chronic neurodegenerative diseases. In the inner ear, epigenetic RNA methylation dysregulation might play a major role in hearing loss, hearing protection and cell regeneration. MA2 is a nonsteroidal anti-inflammatory that blocks FTO binding for m6A containing nucleic acids. Previous in vitro HEI-OC1 cells reported that MA2 application during cisplatin treatment increased cell viability, attenuated induced apoptosis and autophagosome formation and reduced ROS levels [27]. cisplatin after resveratrol, group 3: dexamethasone after cisplatin, group 4: cisplatin after sodium chloride, group 5: cisplatin after dimethylsulfoxide. ABR thresholds valued after cisplatin administration were found to be less affected in rats that had been treated with dexamethasone and resveratrol (P < 0.001). DPOAE values were maintained in rats treated with dexamethasone and resveratrol (P < 0.001) [33].

Other studies
A double blind randomized clinical trial compared N acetylcysteine and Dexamethasone in a population of 57 patients.
Dexamethasone had no effect compared to N-acetylcysteine that shown beneficial results increasing hearing thresholds at higher frequencies such as 4000 and 8000 kHz (p<0.05) [36]. Caffeine has presented a positive correlation in rats exacerbating hearing loss [37]. Recent studies propose a benefit in the use of lithium chlorideinduced autophagy in rats under a cisplatin scheme [38][39][40].
Melatonin has proven to be useful against testicular and kidney cisplatin induced toxicity, but there are few studies that evaluate its otoprotective function in chemotherapy. J de Araujo et. al reported that DPOAE amplitudes in rats treated with cisplatin and melatonin were similar compared to the control group, with significant lower levels in subjects treated with cisplatin alone [41].
Amifostine is an organic phosphate reducing agent that is dephosphorylated into its active thiol metabolite. Its action mechanism is binding to cisplatin metabolites and lower ROS levels. There is no evidence yet to support the otoprotective role of amifostine against cisplatin therapy [42,43]. The threshold change varies between 12.5 ± 2.5 and 0.0 ± 5.0dB from the baseline to day 7, through the frequencies (p <0.001 at the 3 frequencies). (17) The hydrogel provided significant protection against hearing loss induced by cisplatin in mice at 4, 8 and 16 kHz in contrast with the single administration of DEX-cisplatin. [ Preliminary results of the first month of treatment evaluated that group with cisplatin alone had significant damage (p <.05) while the group with vitamin E no, in both groups no changes were found in the ABR. [ MA2 significantly reduced ROS, cell apoptosis and up regulation autophagy. (27) The ototoxicity due to cisplatin represents an important comorbidity, further studies in humans are needed. Clinical trials in humans have compared other ototoxic drugs such as aminoglycosides that also have an important association with ROS production. As the case of aspirin, which had a protective effect against gentamicin, but when its clinical benefits were tested in 94 patients undergoing cisplatin the cumulative dose of 200mg / m2 no significant effect was reported [44] (Table 1).

Conclusion
Different substances and drugs with significant otoprotective results studied in in-vitro phase, promises to initiate experimental animal phase soon. A666-DEX-NP, OTO104 and DEX-SILK dexamethasone formulations showed benefits in experimental animal phase, but still have to be human proved.
Only N-acetylcysteine and Sodium Thiosulfate have reported significant otoprotective effects in human clinical trials. Vitamin E has also shown positive but preliminary results. The substances studied act by different mechanisms but at the end somehow can provide additional protection in cisplatin exposed individuals. This provides a huge opportunity area to appeal the ototoxicity caused by cisplatin.
More comparative studies between proposal otoprotective therapies are needed, although, with the information collected, we can advise decreasing or eliminating caffeine in patients who are under treatment with cisplatin. We also recommend the consumption of antioxidants such as Vitamin E and Vitamin C.
Finally, we recommend a periodic undefined time audiometry during the treatment with cisplatin for the appropriate approach in case of presenting an auditory alteration or to adjust the correct therapeutic dose.