Augmentation of NAD+ by NQO1 attenuates cisplatin-mediated hearing impairment

Abstract

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 β-lapachone (β-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.

The master switchers in the aging of cardiovascular system, reverse senescence by microRNA signatures; as highly conserved molecules

“…SIRT1 has a tight interconnection with DDR switcher PARP (Canto and Auwerx, 2011;Kim et al, 2014). Especially in the heart, the mechanisms of mitochondrial free radical generation is controlled by SIRT1, which deacetylates and activates PGC-1a pathway for orchestrating a complex of events including mitochondria biogenesis, enhanced antioxidant defenses, energetic metabolism and improved fatty acid oxidation to regenerate NADþ/ ATP (Lopez-Otin et al, 2013; Magenta et al, 2013;Zhang and Kraus, 2010).…”

“…Otherwise upon PARP overactivation, cells undergo apoptosis due to over-expression of senescence-associated (SA) miRNAs such as miRNA-34a through p53 activation. There is a double-positive feedback loop between SA-miRNAs over-expression and PARP over-activation (Canto and Auwerx, 2011;Potus et al, 2014;Kim et al, 2014).…”

“…While PARP1 over-activities confront SIRT1 Canto and Auwerx, 2011;Kim et al, 2014), activation of SIRT is protective in aging-related disorders Zhang and Kraus, 2010). In particular, SIRT forms a complex with DDR machinery to deacetylate H3K9Ac and H3K56Ac.…”

“…In response to oxidative stress and inflammatory injury, DNA repair involves PARP1 activity to recruit and assemble the components of DDR machinery, but its over-activation in a feed-forward loop manner can eventually confront SIRT1 activation (Canto and Auwerx, 2011;Potus et al, 2014;Kim et al, 2014).…”

“…Modulating PARP-1 activation protects against hypertrophy response, heart failure, and cardiovascular dysfunction (Yao and Ventura, 2011). PARP1 is linked directly to cellular redox status and oxidative stress by regulating FOXO, the stress resistance TF which extends lifespan in Caenorhabditis elegans Canto and Auwerx, 2011;Potus et al, 2014;Kim et al, 2014).…”