Ginkgolide B protects against cisplatin-induced ototoxicity: enhancement of Akt–Nrf2–HO-1 signaling and reduction of NADPH oxidase

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• 作者：Weijun Ma ; Juan Hu ; Ying Cheng ; Junli Wang…
• 关键词：Ginkgolide B ; Ototoxicity ; Akt ; Nrf2/HO ; 1 ; NADPH oxidase ; Cisplatin
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2015
• 出版时间：May 2015
• 年：2015
• 卷：75
• 期：5
• 页码：949-959
• 全文大小：1,318 KB
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  25.Niture
• 作者单位：Weijun Ma (1)
  Juan Hu (1)
  Ying Cheng (1)
  Junli Wang (1)
  Xiaotong Zhang (1)
  Min Xu (1)
  
  1. Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, XiWu Road 157, Xi’an, 710004, China
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Cancer Research
  Pharmacology and Toxicology
  Oncology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0843

文摘

Cisplatin is a widely used chemotherapeutic drug for the treatment of various cancers. However, the ototoxicity severely limited its maximum dose. The present study was designed to evaluate the effect of Ginkgolide B (GB), a major component of Ginkgo biloba extracts, on cisplatin-induced ototoxicity and to elucidate the molecular mechanism in vitro and in vivo. In HEI-OC1 auditory cells, GB concentration-dependently inhibited the reduction of cell viability and increase in apoptosis exerted by cisplatin. Cisplatin-activated mitochondrial apoptotic molecular events were significantly inhibited by GB. In addition, GB notably suppressed the increase in NOX2 and p47phox expression and the decrease in nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression in cisplatin-exposed cells. Inhibition of Nrf2 using SiRNA and blockage of HO-1 by zinc protoporphyrin IX (ZnPP) suppressed the protective effects of GB. Moreover, GB prevented cisplatin-induced reduction of Akt phosphorylation and LY294002, an inhibitor of PI3?K/Akt signaling, blocked the anti-apoptotic effect of GB in cisplatin-treated cells. Furthermore, the protective effect of GB was tested in cisplatin-exposed rats. GB treatment markedly protected animals against cisplatin-induced hearing loss and vestibular dysfunction. Inhibition of Akt and HO-1 significantly suppressed the improvement in hearing loss and vestibular dysfunction in GB-treated rats. We demonstrate that GB decreases ROS generation through reducing NOX2 expression and enhancing activity through Akt–Nrf2–HO-1 pathway, resulting in inhibition of mitochondrial apoptosis and final reduction of cisplatin-induced ototoxicity in vitro and in vivo. Our findings have gained an insight into the mechanism of GB-exerted protective effect against cisplatin-induced ototoxicity.