Dunnione ameliorates cisplatin-induced small intestinal damage by modulating NAD(+) metabolism.
Although cisplatin is a widely used anticancer drug for the treatment of a variety of tumors, its use is critically limited because of adverse effects such as ototoxicity, nephrotoxicity, neuropathy, and gastrointestinal damage. Cisplatin treatment increases oxidative stress biomarkers in the small intestine, which may induce apoptosis of epithelial cells and thereby elicit damage to the small intestine. Nicotinamide adenine dinucleotide (NAD(+)) is a cofactor for various enzymes associated with cellular homeostasis. In the present study, we demonstrated that the hyper-activation of poly(ADP-ribose) polymerase-1 (PARP-1) is closely associated with the depletion of NAD(+) in the small intestine after cisplatin treatment, which results in downregulation of sirtuin1 (SIRT1) activity. Furthermore, a decrease in SIRT1 activity was found to play an important role in cisplatin-mediated small intestinal damage through nuclear factor (NF)-κB p65 activation, facilitated by its acetylation increase. However, use of dunnione as a strong substrate for the NADH:quinone oxidoreductase 1 (NQO1) enzyme led to an increase in intracellular NAD(+) levels and prevented the cisplatin-induced small intestinal damage correlating with the modulation of PARP-1, SIRT1, and NF-κB. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological NQO1 substrates could be a promising therapeutic approach for protecting against cisplatin-induced small intestinal damage.
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Arpana
A
Pandit
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Hyung-Jin
HJ
Kim
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Gi-Su
GS
Oh
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
AiHua
A
Shen
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Su-Bin
SB
Lee
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Dipendra
D
Khadka
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
SeungHoon
S
Lee
Department of Internal Medicine, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Hyeok
H
Shim
Department of Internal Medicine, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Sei-Hoon
SH
Yang
Department of Internal Medicine, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Eun-Young
EY
Cho
Department of Oriental Medical Physiology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Kang-Beom
KB
Kwon
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, Iksan, Jeonbuk 570-749, Republic of Korea.
Seong-Kyu
SK
Choe
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Raekil
R
Park
Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea. Electronic address: jeanso@wku.ac.kr.
Hong-Seob
HS
So
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; D018836:Inflammation Mediators; D009285:Naphthoquinones; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D009243:NAD; C474009:dunnione; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D002945:Cisplatin
Cisplatin; NAD(+); PARP-1; SIRT1; Small intestinal damage