Roles of NADPH Oxidases in Cisplatin-Induced Reactive Oxygen Species Generation and Ototoxicity

Kim, Hyungjin; Lee, Jeong-Han; Kim, Se-Jin; Oh, Gi‐Su; Moon, Hae-Dalma; Kwon, Kang‐Beom; Park, Channy; Park, Byung Hyun; Lee, Ho-Kyun; Chung, Sung Tae; Park, Raekil; So, Hong-Seob

doi:10.1523/jneurosci.6054-09.2010

Cited by 238 publications

(156 citation statements)

References 36 publications

(48 reference statements)

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“…In our previous study, we also demonstrated that NADPH oxidases (NOXs) played a critical role in cisplatin-induced cochlear injury, and TNF-a and ERK played a key role in NOX activation (41). These findings suggest that inflammation and ROS generation through NOXs are one of the major mechanisms in cisplatin ototoxicity.…”

Section: Figurementioning

confidence: 77%

Activation of Lipopolysaccharide–TLR4 Signaling Accelerates the Ototoxic Potential of Cisplatin in Mice

Kim

Choi

et al. 2011

The Journal of Immunology

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Dysfunction in immune surveillance during anticancer chemotherapy of patients often causes weakness of the host defense system and a subsequent increase in microbial infections. However, the deterioration of organ-specific function related to microbial challenges in cisplatin-treated patients has not yet been elucidated. In this study, we investigated cisplatin-induced TLR4 expression and its binding to LPS in mouse cochlear tissues and the effect of this interaction on hearing function. Cisplatin increased the transcriptional and translational expression of TLR4 in the cochlear tissues, organ of Corti explants, and HEI-OC1 cells. Furthermore, cisplatin increased the interaction between TLR4 and its microbial ligand LPS, thereby upregulating the production of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, via NF-κB activation. In C57BL/6 mice, the combined injection of cisplatin and LPS caused severe hearing impairment compared with that in the control, cisplatin-alone, or LPS-alone groups, whereas this hearing dysfunction was completely suppressed in both TLR4 mutant and knockout mice. These results suggest that hearing function can be easily damaged by increased TLR expression and microbial infections due to the weakened host defense systems of cancer patients receiving therapy comprising three to six cycles of cisplatin alone or cisplatin combined with other chemotherapeutic agents. Moreover, such damage can occur even though patients may not experience ototoxic levels of cumulative cisplatin concentration.

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Section: Figurementioning

confidence: 77%

Activation of Lipopolysaccharide–TLR4 Signaling Accelerates the Ototoxic Potential of Cisplatin in Mice

Kim

Choi

et al. 2011

The Journal of Immunology

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“…Bottone et al (2012) had reported that cisplatin induces cell death in vivo and in vitro in cerebellum and hippocampus of rats. Kim et al (2010) presumed that irreversible cell damage caused by cisplatin might result mainly from oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Tomato pomace powder ameliorated cisplatin-induced microanatomical alterations in brain of Wistar rats

Owoeye¹,

Onwuka²

2015

Int. J. Bio. Chem. Sci

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Cisplatin chemotherapy is associated with neurotoxicity. Oxidative stress has been associated with its pathogenesis. Tomato (Lycopersicon esculentum) pomace powder (TPP) may be a preventive agent by virtue of its known antioxidant property. The possible protective role of TPP against cisplatin-induced alteration of the microanatomy of rat brain was investigated. Thirty rats were divided equally into five groups: control, propylene glycol, TPP, cisplatin (10 mg/kg i.p.); TPP 50 mg/kg plus cisplatin (10 mg/kg i.p.). All administrations were oral by gastric gavage given for 24 days except cisplatin which was given intraperitoneally on days 10 and 17. Rats were euthanized on the 25 th day of treatment. Blood parameters checked, neurobehavioural tests done and brain tissue were examined with regards to micro-anatomical parameters. Cisplatin caused a significant (p<0.05) reduction in lymphocytes. Neurobehavioural results showed that cisplatin caused a reduction in line crossing, rearing and forelimb grip. Cisplatin caused histological alterations in the cerebellum, dentate gyrus and Cornu Ammonis3 (CA3). Co-treatment of cisplatin with TTP ameliorated these haematological, neurobehavioural and histological alterations. In conclusion, Lycopersicon esculentum (as tomato pomace powder) demonstrated neuroprotection against cisplatin-induced alteration of microanatomy of rat cerebellum, dentate gyrus and Cornu Ammonis3 of rat brain.

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“…However, progressive irreversible side effects of cisplatin, including nephrotoxicity and ototoxicity, greatly impair the patient's quality of life and frequently result in the need to lower the dosage during treatment or to discontinue the treatment. Cisplatin ototoxicity primarily occurs in the cochlea, and generally consists of apoptosis-induced damage to the outer hair cells (OHCs), spiral ganglion cells and the marginal cells of the stria vascularis [1,2]. Multiple studies have demonstrated that the inner ear has the capacity to generate an active immune response [3], thereby resulting in hearing loss in some individuals [4].…”

Section: Introductionmentioning

confidence: 99%

Cisplatin ototoxicity involves cytokines and STAT6 signaling network

Kim

Lee

et al. 2011

Cell Res

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We herein investigated the role of the STAT signaling cascade in the production of pro-inflammatory cytokines and cisplatin ototoxicity. A significant hearing impairment caused by cisplatin injection was observed in Balb/c (wild type, WT) and STAT4 −/− , but not in STAT6 −/− mice. Moreover, the expression levels of the protein and mRNA of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, were markedly increased in the serum and cochlea of WT and STAT4 −/− , but not STAT6 −/− mice. Organotypic culture revealed that the shape of stereocilia bundles and arrays of sensory hair cell layers in the organ of Corti from STAT6 −/− mice were intact after treatment with cisplatin, whereas those from WT and STAT4 −/− mice were highly distorted and disarrayed after the treatment. Cisplatin induced the phosphorylation of STAT6 in HEI-OC1 auditory cells, and the knockdown of STAT6 by STAT6-specific siRNA significantly protected HEI-OC1 auditory cells from cisplatin-induced cell death and inhibited pro-inflammatory cytokine production. We further demonstrated that IL-4 and IL-13 induced by cisplatin modulated the phosphorylation of STAT6 by binding with IL-4 receptor alpha and IL-13Rα1. These findings suggest that STAT6 signaling plays a pivotal role in cisplatin-mediated pro-inflammatory cytokine production and ototoxicity.

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Roles of NADPH Oxidases in Cisplatin-Induced Reactive Oxygen Species Generation and Ototoxicity

Cited by 238 publications

References 36 publications

Activation of Lipopolysaccharide–TLR4 Signaling Accelerates the Ototoxic Potential of Cisplatin in Mice

Activation of Lipopolysaccharide–TLR4 Signaling Accelerates the Ototoxic Potential of Cisplatin in Mice

Tomato pomace powder ameliorated cisplatin-induced microanatomical alterations in brain of Wistar rats

Cisplatin ototoxicity involves cytokines and STAT6 signaling network

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