Ginkgolide B protects against cisplatin-induced ototoxicity: enhancement of Akt-Nrf2-HO-1 signaling and reduction of NADPH oxidase.
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 p47(phox) 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.
Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, XiWu Road 157, Xi'an, 710004, China.
Weijun
W
Ma
Juan
J
Hu
Ying
Y
Cheng
Junli
J
Wang
Xiaotong
X
Zhang
Min
M
Xu
D000818:Animals; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D003051:Cochlea / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015834:Cochlear Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D004789:Enzyme Activation / Q000187:drug effects; D046934:Ginkgolides / Q000494:pharmacology*; D034381:Hearing Loss / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D046934:Ginkgolides; D007783:Lactones; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C045856:ginkgolide B; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin