Dunnione ameliorates cisplatin ototoxicity through modulation of NAD(+) metabolism.

Dunnione ameliorates cisplatin ototoxicity through modulation of NAD(+) metabolism. Hear Res. 2015 Sep 1; Authors: Kim HJ, Pandit A, Oh GS, Shen A, Lee SB, Khadka D, Lee S, Shim H, Yang SH, Cho EY, Kwak TH, Choe SK, Park R, So HS 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 f...
Source: Hearing Research - Category: Audiology Authors: Tags: Hear Res Source Type: research