| First Author | Kim HJ | Year | 2014 |
| Journal | Cell Death Dis | Volume | 5 |
| Pages | e1292 | PubMed ID | 24922076 |
| Mgi Jnum | J:318186 | Mgi Id | MGI:6858654 |
| Doi | 10.1038/cddis.2014.255 | Citation | Kim HJ, et al. (2014) Augmentation of NAD(+) by NQO1 attenuates cisplatin-mediated hearing impairment. Cell Death Dis 5:e1292 |
| abstractText | Cisplatin (cis-diaminedichloroplatinum-II) is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as a key regulator of cellular energy metabolism and homeostasis. Here, we demonstrate for the first time that, in cisplatin-mediated ototoxicity, the levels and activities of SIRT1 are suppressed by the reduction of intracellular NAD(+) levels. We provide evidence that the decrease in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) transferase (PARP)-1 activation and microRNA-34a through p53 activation aggravates cisplatin-mediated ototoxicity. Moreover, we show that the induction of cellular NAD(+) levels using beta-lapachone (beta-Lap), whose intracellular target is NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity. |
