Dunnione ameliorates cisplatin ototoxicity through modulation of NAD(+) metabolism.
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.
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Hyung-Jin
HJ
Kim
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Arpana
A
Pandit
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Gi-Su
GS
Oh
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
AiHua
A
Shen
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Su-Bin
SB
Lee
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Dipendra
D
Khadka
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
SeungHoon
S
Lee
Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Hyeok
H
Shim
Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Sei-Hoon
SH
Yang
Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Eun-Young
EY
Cho
PAEAN Biotechnology, 160 Techno-2 Street, Yuseong-gu, Daejeon, 305-500, Republic of Korea.
Tae Hwan
TH
Kwak
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Seong-Kyu
SK
Choe
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea.
Raekil
R
Park
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University School of Medicine, Iksan, Jeonbuk, 570-749, Republic of Korea. Electronic address: jeanso@wku.ac.kr.
Hong-Seob
HS
So
D000107:Acetylation; D000818:Animals; D002945:Cisplatin; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D019610:Cytoprotection; D004195:Disease Models, Animal; D006309:Hearing / Q000187:drug effects*; D034381:Hearing Loss / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency / Q000235:genetics; D009285:Naphthoquinones / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D009285:Naphthoquinones; D020011:Protective Agents; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D009243:NAD; C474009:dunnione; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D002945:Cisplatin
Cisplatin; NAD(+); Ototoxicity; PARP-1; SIRT1