| Literature DB >> 16485034 |
H-S So1, H-J Kim, J-H Lee, J-H Lee, S-Y Park, C Park, Y-H Kim, J-K Kim, K-M Lee, K-S Kim, S-Y Chung, W-C Jang, S-K Moon, H-T Chung, R-K Park.
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, GST micro-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.Entities:
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Year: 2006 PMID： 16485034 DOI： 10.1038/sj.cdd.4401863
Source DB: PubMed Journal: Cell Death Differ ISSN： 1350-9047 Impact factor: 15.828