KSR1 knockout mouse model demonstrates MAPK pathway's key role in cisplatin- and noise-induced hearing loss

Journal of Neuroscience, Journal Year: 2024, Volume and Issue: unknown, P. e2174232024 - e2174232024

Published: March 28, 2024

Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit large portion of the world population. Here we found that mice devoid protein kinase suppressor RAS 1 (KSR1) their tissues (germline KO mice) exhibit resistance both cisplatin- noise-induced permanent compared wild-type KSR1 littermates. scaffold brings proximity mitogen-activated (MAPK) proteins BRAF, MEK1/2 ERK1/2 assists activation through phosphorylation cascade induced by cisplatin noise insults cochlear cells. KSR1, MEK1/2, are all ubiquitously expressed cochlea. Deleting tempered down MAPK cells following conferred protection up 30 dB SPL three tested frequencies male female mice. Treatment with dabrafenib, an FDA-approved oral BRAF inhibitor, protected from loss. Dabrafenib treatment did not enhance mice, providing evidence dabrafenib works primarily pathway. Thus, either elimination gene expression or drug inhibition cellular pathway resulted profound noise-induce Inhibition pathway, responds damage cells, can prove valuable strategy treat Significance Statement Ten percent population suffers but this impairment may be preventable. We show (KO) littermates harbor protein. Removing tempers BRAF-MEK-ERK cochlea insults. and, importantly, confer additional Hence, has unique role responding removing results protection.

Language: Английский

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Apoptosis, autophagy, ferroptosis, and pyroptosis in cisplatin-induced ototoxicity and protective agents

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 24, 2024

Cisplatin is widely used to treat various solid tumors. However, its toxicity normal tissues limits clinical application, particularly due ototoxic effects, which can result in hearing loss patients undergoing chemotherapy. While significant progress has been made preclinical studies elucidate the cellular and molecular mechanisms underlying cisplatin-induced ototoxicity (CIO), precise remain unclear. Moreover, optimal protective agent for preventing or mitigating yet be identified. This review summarizes current understanding of roles apoptosis, autophagy, ferroptosis, pyroptosis, agents ototoxicity. A deeper these cell death inner ear, along with agents, could facilitate translation into therapeutics, help identify new therapeutic targets, provide novel strategies cisplatin-based cancer treatment.

Language: Английский

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Otoprotective Effects of Sodium Thiosulfate by Demographic and Clinical Characteristics: A Report From Children's Oncology Group Study ACCL0431

Pediatric Blood & Cancer, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

ABSTRACT Background ACCL0431 was a randomized clinical trial that demonstrated efficacy of sodium thiosulfate (STS) for preventing cisplatin‐induced hearing loss (CIHL) among patients 1–18 years old. The purpose this study to evaluate possible differential STS otoprotection patient subgroups. Procedure This secondary analysis included participants treated with cisplatin and receive or not (observation). Hearing status obtained at 4 weeks 12 months post therapy (SIOP Ototoxicity Scale). Cumulative incidence CIHL (Grade 1+) assessed across age, sex, race/ethnicity, cancer diagnosis, infusion duration. Associations between these variables were using multivariable logistic regression. Interaction terms used potential heterogeneity in effect sizes Results Among evaluable ( n = 121), 22.4% 54.0% observation. Odds developing greatest children less than 5 versus older (randomization‐adjusted odds ratio [OR] 2.94, 95% CI: 1.30–7.14) those neuroblastoma, hepatoblastoma, medulloblastoma germ cell tumor osteosarcoma (age‐ randomization‐adjusted OR 11.26, 3.08–47.35). otoprotective also the same highest risk groups by age (<5 years: 0.08, 0.02–0.32; ≥5 0.39, 0.15–1.06) diagnosis (neuroblastoma/hepatoblastoma/medulloblastoma: 0.1, 0.02–0.45; tumor/osteosarcoma: 0.32, 0.06–1.25). Significant from noted other subgroups varied magnitudes effect. Conclusions appears differ clinically meaningful subgroups, particularly diagnosis. These results inform decision‐making future research.

Language: Английский

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Oseltamivir (Tamiflu), a Commonly Prescribed Antiviral Drug, Mitigates Hearing Loss in Mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 8, 2024

Hearing loss affects up to 10% of all people worldwide, but currently there is only one FDA-approved drug for its prevention in a subgroup cisplatin-treated pediatric patients. Here, we performed an unbiased screen 1,300 drugs protection against cisplatin-induced cell death inner ear line, and identified oseltamivir phosphate (brand name Tamiflu), common influenza antiviral drug, as top candidate. Oseltamivir was found be otoprotective by oral delivery multiple established cisplatin noise exposure mouse models. The conferred permanent hearing 15-25 dB SPL both female male mice. treatment reduced mice outer hair cells after mitigated cochlear synaptopathy exposure. A potential binding protein, ERK1/2, associated with inflammation, shown activated cotreatment explants. Importantly, the number infiltrating immune cochleae post exposure, were significantly treatment, suggesting anti-inflammatory mechanism action. Our results support oseltamivir, widespread low side effects, promising therapeutic candidate chemotherapy traumatic

Language: Английский

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FDA-Approved MEK1/2 Inhibitor, Trametinib, Protects Mice from Cisplatin and Noise-Induced Hearing Loss

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 21, 2024

Hearing loss is one of the most common types disability; however, there only FDA-approved drug to prevent any type hearing loss. Treatment with highly effective chemotherapy agent, cisplatin, and exposure high decibel noises are two causes The mitogen activated protein kinase (MAPK) pathway, a phosphorylation cascade consisting RAF, MEK1/2, ERK1/2, has been implicated in both Pharmacologically inhibiting BRAF or ERK1/2 protective from noise cisplatin-induced multiple mouse models. Trametinib, MEK1/2 inhibitor, protects cisplatin induced outer hair cell death cochlear explants; best our knowledge, not yet shown be

Language: Английский

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Trametinib, a MEK1/2 Inhibitor, Protects Mice from Cisplatin- and Noise-Induced Hearing Loss

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(6), P. 735 - 735

Published: June 5, 2024

Hearing loss is one of the most common types disability; however, there only FDA-approved drug to prevent any type hearing loss. Treatment with highly effective chemotherapy agent, cisplatin, and exposure high-decibel noises are two causes The mitogen-activated protein kinase (MAPK) pathway, a phosphorylation cascade consisting RAF, MEK1/2, ERK1/2, has been implicated in both Pharmacologically inhibiting BRAF or ERK1/2 protective against noise- cisplatin-induced multiple mouse models. Trametinib, MEK1/2 inhibitor, protects from outer hair cell death cochlear explants; best our knowledge, not yet shown be vivo. In this study, we demonstrate that trametinib translationally relevant model does interfere cisplatin's tumor-killing efficacy cancer lines. Higher doses were toxic mice when combined but lower without known toxicity. Trametinib also protected noise-induced synaptic damage. This study shows inhibition insults loss, as well targeting all three kinases MAPK pathway cisplatin-

Language: Английский

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Oseltamivir (Tamiflu), a commonly prescribed antiviral drug, mitigates hearing loss in mice

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(8)

Published: Aug. 1, 2024

Dear Editor, Hearing loss affects up to 10% of people worldwide and therapeutic interventions are desperately needed. Noise exposure chemotherapy treatments leading causes this impairment, but currently there is only one FDA-approved drug for a subgroup cisplatin-treated cancer patients.1, 2 can arise from damage many different inner ear cell types with outer hair (OHC) synaptic dysfunction as two the most common aetiologies hearing loss.2-4 Drug repurposing strategy addressing unmet medical needs that be quicker more cost-effective than traditional development.3 Here, we performed unbiased cell-based screens 1300 drugs tested our top candidate oseltamivir phosphate (brand name Tamiflu), influenza antiviral drug, in established cisplatin- noise-induced animal models. Our results support promising otoprotective both cisplatin traumatic noise exposure. Oseltamivir its active form, carboxylate, protect against cisplatin-induced mouse cochlear explants without interfering cisplatin's tumour killing efficacy lines. The prodrug, phosphate, at dose 3 µM, was hit high-throughput reducing 95% caspase-3/7 death activity cells.3, 4 In P3 explants, protected OHC an EC50 450 nM (Figure 1A,D), while carboxylate 1B), had similar 505 1C,E). Importantly, cotreatment three small lung carcinoma neuroblastoma lines did not interfere ability kill cells 1F–K). protects mice ototoxicity after single, high clinically relevant, multicycle protocol. Adult FVB/NJ were treated orally 50 mg/kg 45 min before 30 2A). We measured auditory brainstem response (ABR) test function. ABR measures nerve electrical activities cochleae brain. threshold lowest decibel sound pressure level (dB SPL) hear at. Mice cotreated 15 dB lower shifts 32 kHz region displayed reduction middle basal regions compared 2B–E). Utilising relevant model mimics treatment humans 2F),4-6 50, 10 or oseltamivir, morning 12 h later consecutive days. An amount administered via intraperitoneal injection. significantly 16 regions, no difference alone 2G,H). higher wave 1 amplitudes 90 2L), distortion product otoacoustic emission (DPOAE) 2I). cotreatments conferred significant OHCs 2J,K) weight 2M). Oral therapy synaptopathy. Mice, females males, who received 100 24 3A) exhibited reduced relative carrier-treated 3B–D). protection 8 3E). No observed group 3F). DPOAE 3G–I). Three-day sufficient maximum effects when initiated dB, 2-h exposure, achieved 106 insult S1). portrayed average amplitude 80 SPL number Ctbp2 puncta exposed 3J–L). otoprotection partially mediated through inhibition pERK protein levels associated CD45-positive immune noise-exposed mice. Given known binding viral neuraminidase, whether would inhibit mammalian neuraminidases. Cochlear N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (DANA), pan-selective neuraminidase inhibitor, zanamivir, older has greater off-target affinity neuraminidases 4A–D).7 Neither DANA nor zanamivir 4A–D), indicating oseltamivir's inhibition. Next, submitted chemical structures pro-drug, metabolite, target prediction server based on data, SuperPRED.8 ERK2 NF-kB p105 hits compounds probability coefficient exceeding .95 4E,F). mean fluorescence µM 4G,H). To decreases inflammation following their collected days post-exposure 4I). Noise-exposed per section (37) non-noise carrier (16) (14) twice daily (25) 4J,K). widely used good safety profile.9 given day, which 66% equivalent standard adult dose.10 These demonstrate preclinical data repurposed loss. Tal Teitz, Duane Currier, Jian Zuo Taosheng Chen designed screens. Matthew A. Ingersoll Richard D. Lutze vivo experiments. Emma J. Sailor-Longsworth Regina G. Kelmann dissections, counts. Sailor-Longsworth, Kristina Ly Kelmann, analysed data. imaged CD45-stained cryosections. interference testing Ingersoll, Lutze, Teitz involved analysis design study. Ly, wrote manuscript input all authors. thank Daniel Kresock, Dr. Christy Howe, Janee Gelineau van Waes, Kristen Drescher, Pat Steele, Ann Bryen Creighton University ARF staff assistance studies. T.T. J.Z. inventors provisional patent applications filed use #18/129267, #18/106918, co-founders Ting Therapeutics LLC. All other authors declare they have competing interests. research funded by grants: Department Defense Award #W81XWH-21-1-0696 (grant RH200032), LB 506 Nebraska State, Health Human Services, Cancer Smoking Disease Research Program, National Institutes NIDCD 1R01DC018850) American Foundation 2020 grant Teitz. This investigation conducted facilities constructed Facilities Improvement Program (G20 RR024001-01) Center Resources, NIH. Auditory Vestibular Technology Core University, Omaha, NE (RRID: SCR_023866). facility supported School Medicine grants GM103427 GM139762 Institute General Medical Science (NIGMS), component (NIH). IBIF Resources (RR016469) NIGMS (GM103427). #1076 Scintillon Institute. solely responsibility does necessarily represent official views needed evaluate conclusions paper present and/or Supporting Information. Please note: publisher responsible content functionality any supporting information supplied Any queries (other missing content) should directed corresponding author article.

Language: Английский

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KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 13, 2023

Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit large portion of the world population. Here we found that mice devoid protein kinase suppressor RAS 1 (KSR1) their tissues (germline KO mice) exhibit resistance both cisplatin- noise-induced permanent compared wild-type KSR1 littermates. expressed cochlea scaffold brings proximity mitogen-activated (MAPK) proteins BRAF, MEK ERK assists activation through phosphorylation cascade induced by cisplatin noise insults cochlear cells. Deleting tempered down MAPK cells following conferred protection up 30 dB SPL three tested frequencies mice. Treatment with dabrafenib, an FDA-approved oral BRAF inhibitor, downregulated protected from loss. Dabrafenib treatment did not enhance mice, as excepted, providing evidence dabrafenib works primarily pathway. Thus, either elimination gene expression or drug inhibition cellular pathway resulted profound noise-induce Inhibition pathway, responds damage cells, can prove valuable strategy treat

Language: Английский

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