title: 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.
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea.
authors.forename: G-S
authors.initials: GS
authors.lastname: Oh
authors.affiliation: 1] Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea [2] BK21plus Program and Department of Smart Life-Care Convergence, Wonkwang University Graduate School, Jeonbuk, Republic of Korea.
authors.forename: A
authors.initials: A
authors.lastname: Shen
authors.affiliation: 1] Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea [2] BK21plus Program and Department of Smart Life-Care Convergence, Wonkwang University Graduate School, Jeonbuk, Republic of Korea.
authors.forename: S-B
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea.
authors.forename: S-K
authors.initials: SK
authors.lastname: Choe
authors.affiliation: 1] Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea [2] BK21plus Program and Department of Smart Life-Care Convergence, Wonkwang University Graduate School, Jeonbuk, Republic of Korea [3] Department of Oriental Medical Physiology, College of Korean Medicine, Wonkwang University, Jeonbuk, Republic of Korea.
authors.forename: K-B
authors.initials: KB
authors.lastname: Kwon
authors.affiliation: Life Science Research Center, KT&G Life Sciences, Suwon, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Life Science Research Center, KT&G Life Sciences, Suwon, Republic of Korea.
authors.forename: K-S
authors.initials: KS
authors.lastname: Seo
authors.affiliation: Life Science Research Center, KT&G Life Sciences, Suwon, Republic of Korea.
authors.forename: T H
authors.initials: TH
authors.lastname: Kwak
authors.affiliation: 1] Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea [2] BK21plus Program and Department of Smart Life-Care Convergence, Wonkwang University Graduate School, Jeonbuk, Republic of Korea.
authors.forename: R
authors.initials: R
authors.lastname: Park
authors.affiliation: 1] Center for Metabolic Function Regulation, Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, Republic of Korea [2] BK21plus Program and Department of Smart Life-Care Convergence, Wonkwang University Graduate School, Jeonbuk, Republic of Korea.
authors.forename: H-S
authors.initials: HS
authors.lastname: So
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D034381:Hearing Loss / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009243:NAD / Q000235:genetics / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D009243:NAD; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D002945:Cisplatin