Dunnione ameliorates cisplatin ototoxicity through modulation of NAD(+) metabolism.
Hear Res
; 333: 235-246, 2016 Mar.
Article
em En
| MEDLINE
| ID: mdl-26341473
ABSTRACT
Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that cisplatin-induced ototoxicity is 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 an important regulator of energy metabolism and cellular homeostasis. Here, we demonstrate that the levels and activities of sirtuin-1 (SIRT1) are suppressed by the reduction of intracellular NAD(+) levels in cisplatin-mediated ototoxicity. We provide evidence that the decreases in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) polymerase-1 (PARP-1) activation and microRNA-34a levels through cisplatin-mediated p53 activation aggravate the associated ototoxicity. Furthermore, we show that the induction of cellular NAD(+) levels using dunnione, which targets intracellular 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Naftoquinonas
/
Cisplatino
/
Cóclea
/
Substâncias Protetoras
/
Audição
/
Perda Auditiva
/
NAD
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Hear Res
Ano de publicação:
2016
Tipo de documento:
Article