Dimethyl Sulfoxide (DMSO) Exacerbates Cisplatin-induced Sensory Hair Cell Death in Zebrafish (Danio rerio)

Uribe, Phillip M.; Mueller, Mark; Gleichman, Julia S.; Kramer, Matthew D.; Wang, Qi; Sibrian‐Vazquez, Martha; Strongin, Robert M.; Steyger, Peter S.; Cotanche, Douglas A.; Matsui, Jonathan I.

doi:10.1371/journal.pone.0055359

Cited by 38 publications

(46 citation statements)

References 32 publications

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“…In order to determine if gentamicin can reach the inner ear organs, adult Brn3c-GFP transgenic zebrafish were given a single intraperitoneal injection of Texas Red-conjugated gentamicin (GTTR) and allowed to recover for 4 hours. These zebrafish express green fluorescent protein (GFP) in the cell membranes of sensory hair cells [20], [30], [31]. The zebrafish were then sacrificed, the head fixed and the inner ear organs were dissected, mounted, and imaged.…”

Section: Resultsmentioning

confidence: 99%

“…Transgenic TG (Brn3c:GAP43-GFP) s356t fish on the TL background (AKA Brn3c-GFP zebrafish ( Danio rerio ), a gift from Dr. Herwig Baier, University of California, San Francisco) [20], [30], [31], or wildtype zebrafish obtained from commercial suppliers were used for these experiments. Zebrafish were maintained on a 14 hour light/10 hour dark cycle using standard procedures [32].…”

Section: Methodsmentioning

confidence: 99%

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Aminoglycoside-Induced Hair Cell Death of Inner Ear Organs Causes Functional Deficits in Adult Zebrafish (Danio rerio)

et al. 2013

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Aminoglycoside antibiotics, like gentamicin, kill inner ear sensory hair cells in a variety of species including chickens, mice, and humans. The zebrafish (Danio rerio) has been used to study hair cell cytotoxicity in the lateral line organs of larval and adult animals. Little is known about whether aminoglycosides kill the hair cells within the inner ear of adult zebrafish. We report here the ototoxic effects of gentamicin on hair cells in the saccule, the putative hearing organ, and utricle of zebrafish. First, adult zebrafish received a single 30 mg/kg intraperitoneal injection of fluorescently-tagged gentamicin (GTTR) to determine the distribution of gentamicin within inner ear sensory epithelia. After 4 hours, GTTR was observed in hair cells throughout the saccular and utriclar sensory epithelia. To assess the ototoxic effects of gentamicin, adult zebrafish received a single 250 mg/kg intraperitoneal injection of gentamicin and, 24 hours later, auditory evoked potential recordings (AEPs) revealed significant shifts in auditory thresholds compared to untreated controls. Zebrafish were then euthanized, the inner ear fixed, and labeled for apoptotic cells (TUNEL reaction), and the stereociliary bundles of hair cells labeled with fluorescently-tagged phalloidin. Whole mounts of the saccule and utricle were imaged and cells counted. There were significantly more TUNEL-labeled cells found in both organs 4 hours after gentamicin injection compared to vehicle-injected controls. As expected, significantly fewer hair cell bundles were found along the rostral-caudal axis of the saccule and in the extrastriolar and striolar regions of the utricle in gentamicin-treated animals compared to untreated controls. Therefore, as in other species, gentamicin causes significant inner ear sensory hair cell death and auditory dysfunction in zebrafish.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Aminoglycoside-Induced Hair Cell Death of Inner Ear Organs Causes Functional Deficits in Adult Zebrafish (Danio rerio)

et al. 2013

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“…When dissolved in DMSO, two platinum atoms bound to His15, leading to the conclusion that DMSO could facilitate platinum-protein binding (50). Uribe et al reported increased sensory hair cell death in zebrafish co-treated with cisplatin and DMSO but not other solvents, which was ascribed to the cell permeabilizing effects of DMSO, and warned that DMSO could produce false-positive effects in other drug screens due to DMSO's biological activity (51). …”

Section: Discussionmentioning

confidence: 99%

Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin, and Other Platinum Complexes

et al. 2014

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The platinum drugs cisplatin, carboplatin and oxaliplatin are highly utilized in the clinic and as a consequence are extensively studied in the laboratory setting. In this study, we examined the literature and found a significant number of studies (11 - 34%) in prominent cancer journals utilizing cisplatin dissolved in dimethylsulfoxide (DMSO). However, dissolving cisplatin in DMSO for laboratory-based studies results in ligand displacement and changes the structure of the complex. We examined the effect of DMSO on platinum complexes, including cisplatin, carboplatin and oxaliplatin, finding that DMSO reacted with the complexes, inhibited their cytotoxicity and their ability to initiate cell death. These results render a substantial portion of the literature on cisplatin uninterpretable. Raising awareness of this significant issue in the cancer biology community is critical, and we make recommendations on appropriate solvation of platinum drugs for research.

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“…Having shown that TLR4 played a critical role mediating cisplatin ototoxicity responses in vitro we sought to examine the role of TLR4 in an in vivo CIO model. We chose to use zebrafish because it is a robust and widely-accepted model of ototoxicity (46)(47)(48)(49)(50)(51)(52). Using established assays, we scored the health of neuromasts, which are mechanotransducing hair cells that bear structural, cellular, and physiological similarities 10…”

Section: Zebrafish Homologs Of Tlr4 Are Required For Cisplatin-inducementioning

confidence: 99%

Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity

Babolmorad¹,

Latif²,

Pollock

et al. 2020

Preprint

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Toll-like receptor 4 (TLR4) is famous for recognizing the bacterial endotoxin lipopolysaccharide (LPS) as its canonical ligand. TLR4 is also activated by other classes of agonist including some Group 9/10 transition metals. Roles for these non-canonical ligands in pathobiology mostly remain obscure, though TLR4 interactions with metals 5 can mediate immune hypersensitivity reactions. In this work, we tested whether TLR4 can be activated by the Group 10 transition metal, platinum. We demonstrated that in the presence of TLR4, platinum activates pathways downstream of TLR4 to a similar extent as the known TLR4 agonists LPS and nickel. Platinum is the active moiety in cisplatin, a very potent and invaluable chemotherapeutic used to treat solid tumors in childhood 10 cancer patients. Unfortunately, cisplatin use is limited due to an adverse effect of permanent hearing loss (cisplatin-induced ototoxicity, CIO). Herein, we demonstrated that cisplatin also activates TLR4, prompting the hypothesis that TLR4 mediates aspects of CIO. Cisplatin activation of TLR4 was independent of the TLR4 co-receptors CD14 and MD-2, which is consistent with TLR4 signaling elicited by transition metals. We 15 found that TLR4 is required for cisplatin-induced inflammatory, oxidative and apoptotic responses in an ear outer hair cell line and for hair cell damage in vivo. Thus, TLR4 is a promising therapeutic target to mitigate CIO. We additionally identify a TLR4 small molecule inhibitor able to curtail cisplatin toxicity in vitro. Further work is warranted towards inhibiting TLR4 as a route to mitigating this adverse outcome of childhood 20 cancer treatment. Significance StatementThis work identifies platinum, and its derivative cisplatin, as new agonists for TLR4. TLR4 contributes to cisplatin-induced hair cell death in vitro and in vivo. Genetic and 25 small molecule inhibition of TLR4 identify this receptor as a druggable therapeutic target with promise to curtail cisplatin-induced ototoxicity, a devastating side-effect of an otherwise invaluable chemotherapeutic tool.

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Dimethyl Sulfoxide (DMSO) Exacerbates Cisplatin-induced Sensory Hair Cell Death in Zebrafish (Danio rerio)

Cited by 38 publications

References 32 publications

Aminoglycoside-Induced Hair Cell Death of Inner Ear Organs Causes Functional Deficits in Adult Zebrafish (Danio rerio)

Aminoglycoside-Induced Hair Cell Death of Inner Ear Organs Causes Functional Deficits in Adult Zebrafish (Danio rerio)

Say No to DMSO: Dimethylsulfoxide Inactivates Cisplatin, Carboplatin, and Other Platinum Complexes

Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity

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