title: Erdosteine protects HEI-OC1 auditory cells from cisplatin toxicity through suppression of inflammatory cytokines and induction of Nrf2 target proteins.
abstract: Cisplatin has many adverse effects, which are a major limitation to its use, including ototoxicity, neurotoxicity, and nephrotoxicity. This study aims to elucidate the protective mechanisms of erdosteine against cisplatin in HEI-OC1 cells. Pretreatment with erdosteine protects HEI-OC1 cells from cisplatin-medicated apoptosis, which is characterized by increase in nuclear fragmentation, DNA laddering, sub-G0/G1 phase, H2AX phosphorylation, PARP cleavage, and caspase-3 activity. Erdosteine significantly suppressed the production of reactive nitrogen/oxygen species and pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in cisplatin-treated cells. Studies using pharmacologic inhibitors demonstrated that phosphatidylinositol-3-kinases (PI3K) and protein kinase B (Akt) have protective roles in the action of erdosteine against cisplatin in HEI-OC1 cells. In addition, pretreatment with erdosteine clearly suppressed the phosphorylation of p53 (Ser15) and expression of p53-upregulated modulator of apoptosis. Erdosteine markedly induces expression of NF-E2-related factor 2 (Nrf2), which may contribute to the increase in expression of glutathione redox genes γ-l-glutamate-l-cysteine-ligase catalytic and γ-l-glutamate-l-cysteine-ligase modifier subunits, as well as in the antioxidant genes HO-1 and SOD2 in cisplatin-treated HEI-OC1 cells. Furthermore, the increase in expression of phosphorylated p53 induced by cisplatin is markedly attenuated by pretreatment with erdosteine in the mitochondrial fraction. This increased expression may inhibit the cytosolic expression of the apoptosis-inducing factor, cytochrome c, and Bax/Bcl-xL ratio. Thus, our results suggest that treatment with erdosteine is significantly attenuated cisplatin-induced damage through the activation of Nrf2-dependent antioxidant genes, inhibition of pro-inflammatory cytokines, activation of the PI3K/Akt signaling, and mitochondrial-related inhibition of pro-apoptotic protein expression in HEI-OC1 auditory cells.
authors.affiliation: Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University, College of Medicine, 460 Iksandae-ro, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Channy
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University, College of Medicine, 460 Iksandae-ro, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Joon No
authors.initials: JN
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, Wonkwang University, College of Medicine, 460 Iksandae-ro, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Lim
authors.affiliation: Department of Obstetrics and Gynecology, Wonkwang University, College of Medicine, 460 Iksandae-ro, Iksan, Jeonbuk 570-749, Republic of Korea.
authors.forename: Gi-Yeon
authors.initials: GY
authors.lastname: Hong
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Sung K
authors.initials: SK
authors.lastname: Moon
authors.affiliation: Department of Head and Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.affiliation: Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University, College of Medicine, 460 Iksandae-ro, Iksan, Jeonbuk 570-749, Republic of Korea. Electronic address: seongkyu642@wku.ac.kr.
authors.forename: Seong-Kyu
authors.initials: SK
authors.lastname: Choe
authors.affiliation: Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University, College of Medicine, 460 Iksandae-ro, Iksan, Jeonbuk 570-749, Republic of Korea. Electronic address: rkpark@wku.ac.kr.
authors.forename: Raekil
authors.initials: R
authors.lastname: Park
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D007758:Ear, Inner / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013864:Thioglycolates / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013864:Thioglycolates; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; C048498:erdosteine; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin