Abstract
We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GSTĪ¼-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.
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Abbreviations
- ROS:
-
reactive oxygen species
- wt-Nrf:
-
wild type Nrf2
- DN-Nrf2:
-
dominant negative Nrf2
- CoPPIX:
-
Cobalt protoporphyrin IX
- SnPPIX:
-
tin protoporphyrin IX
- HO-1:
-
heme oxygenase-1
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Acknowledgements
This work was supported by the Korea Science & Engineering Foundation (KOSEF) through the Vestibulocochlear Research Center (VCRC) at Wonkwang University in 2005.
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So, HS., Kim, HJ., Lee, JH. et al. Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin. Cell Death Differ 13, 1763ā1775 (2006). https://doi.org/10.1038/sj.cdd.4401863
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DOI: https://doi.org/10.1038/sj.cdd.4401863
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