Erdosteine protects HEI-OC1 auditory cells from cisplatin toxicity through suppression of inflammatory cytokines and induction of Nrf2 target proteins
| Autor: | Channy Park, Seong Kyu Choe, David J. Lim, Sung K. Moon, Gi yeon Hong, Joon No Lee, Se-Jin Kim, Hyewon Lim, Raekil Park |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
NF-E2-Related Factor 2
Anti-Inflammatory Agents Erdosteine Apoptosis Thiophenes DNA laddering Pharmacology Transfection Toxicology Antioxidants Cell Line Proinflammatory cytokine Mice medicine Animals Protein Kinase Inhibitors Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Cisplatin Dose-Response Relationship Drug Chemistry Reactive Nitrogen Species Mitochondria Oxidative Stress Gene Expression Regulation Biochemistry Cytoprotection Ear Inner Thioglycolates Cytokines RNA Interference Tumor necrosis factor alpha Inflammation Mediators Phosphatidylinositol 3-Kinase Tumor Suppressor Protein p53 Apoptosis Regulatory Proteins Reactive Oxygen Species Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | Toxicology and Applied Pharmacology. 288:192-202 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2015.07.014 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect