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Cancer Chemotherapy and Pharmacology

, Volume 75, Issue 5, pp 949–959 | Cite as

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

  • Weijun Ma
  • Juan Hu
  • Ying Cheng
  • Junli Wang
  • Xiaotong Zhang
  • Min XuEmail author
Original Article

Abstract

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.

Keywords

Ginkgolide B Ototoxicity Akt Nrf2/HO-1 NADPH oxidase Cisplatin 

Abbreviation

CHIP

Chromatin immunoprecipitations

Cyto C

Cytochrome c

GB

Ginkgolide B

HEI-OC1

House Ear Institute-Organ of Corti 1

HO-1

Heme oxygenase-1

NOX

Nicotinamide adenine dinucleotide phosphate oxidase

MMP

Mitochondrial membrane potential

Nrf2

Nuclear factor erythroid 2-related factor 2

PARP

Poly (ADP-ribose) polymerase

PBS

Phosphate-buffered saline

qRT-PCR

Real-time polymerase chain reaction

Rho123

Rhodamine 123

TUNEL

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

ZnPP

Zinc protoporphyrin IX

Notes

Conflict of interest

None.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Weijun Ma
    • 1
  • Juan Hu
    • 1
  • Ying Cheng
    • 1
  • Junli Wang
    • 1
  • Xiaotong Zhang
    • 1
  • Min Xu
    • 1
    Email author
  1. 1.Department of Otolaryngology Head and Neck SurgeryThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina

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