The curcuminoid, EF-24, reduces cisplatin-mediated reactive oxygen species in zebrafish inner ear auditory and vestibular tissues

Abstract

Cisplatin is a widely used chemotherapy drug that can damage auditory and vestibular tissue and cause hearing and balance loss through the intracellular release of reactive oxygen species (ROS). Curcumin has anticancer efficacy and can also counteract cisplatin's damaging effect against sensory tissue by scavenging intracellular ROS, but curcumin's applicability is limited due to its low bioavailability. EF-24 is a synthetic curcumin analog that is more bioavailable than curcumin and can target cancer, but its effects against cisplatin-mediated ROS in auditory and vestibular tissue is currently unknown. In this study, we employed a novel zebrafish inner ear tissue culture system to determine if EF-24 counteracted cisplatin-mediated ROS release in two sensory endorgans, the saccule and the utricle. The zebrafish saccule is associated with auditory function and the utricle with vestibular function. Trimmed endorgans were placed in tissue culture media with a fluorescent reactive oxygen species indicator dye, and intracellular ROS release was measured using a spectrophotometer. We found that cisplatin treatment significantly increased ROS compared to controls, but that EF-24 treatment did not alter or even decreased ROS. Importantly, when equimolar cisplatin and EF-24 treatments are combined, ROS did not increase compared to controls. This suggests that EF-24 may be able to prevent intracellular ROS caused by cisplatin treatment in inner ear tissue.

Use of Zebrafish in Drug Discovery Toxicology

“…Some methods, through live imaging and forward genetic screens, can provide insight into the chemical and genetic mechanisms of ototoxicity as well as information about whether a protective cotreatment interferes with the therapy . The following are some examples of protective cotreatments discovered using this model: for radiotherapy for head and neck cancer, p38 inhibition; to mitigate cisplatin-induced ototoxiticy, quercetin, curcuminoids, CDK2 inhibition, or sirtuin 1 activation; for neomycin ototoxicity, melatonin, astaxanthin nanoemulsion; and recently discovered potential aminoglycoside-protective cotreatments. , The latter work resulted in repurposing a preapproved drug into clinical trials for aminoglycoside protection, demonstrating the utility for zebrafish to help advance discoveries that circumvent human ototoxicity.…”

“…The pharmaceutical mechanism studies have revealed cell types, pathways, and genes involved in cardiovascular, , neuromuscular, neuronal, − ocular, auditory, ,− and embryo-development − toxicities. Those same studies introduce models by which safer compounds can be discovered by conducting SAR within or around a chemical series as has been lately shown for several chemotherapies. − Equally important, those models can be used to interrogate species-specific mechanisms of toxicities, which is of great value for predicting clinical toxicity.…”

Progress in protecting vestibular hair cells

“…Cisplatin-induced oxidative stress Monroe et al (2018) reported that after 100 μM cisplatin treatment, the ROS increased dramatically in saccular and utricular tissues of zebrafish. The release of ROS was sharply elevated as cisplatin's concentrations increased to 500 μM (Monroe et al 2018).…”

“…Cisplatin-induced oxidative stress Monroe et al (2018) reported that after 100 μM cisplatin treatment, the ROS increased dramatically in saccular and utricular tissues of zebrafish. The release of ROS was sharply elevated as cisplatin's concentrations increased to 500 μM (Monroe et al 2018). The generation of ROS in the vestibular epithelium caused by cisplatin has been reported to cause vestibular HCs to undergo apoptosis (Tian et al 2013).…”

“…Other factors have been shown to reduce cisplatin-induced ROS in vestibular organs, including D-methionine (Cheng et al 2006 ), which can reduce cisplatin-induced LPO and NO in the vestibular HCs of guinea pigs, and EF-24(bis[(2-fluorophenyl)methylene]-4-piperidinone) (Monroe et al 2018 ) which can decrease ROS release by cisplatin treatment in the maculae of zebrafish. However, further investigation is required to understand the protective effects of D-methionine and EF-24 on vestibular HCs.…”