1. Academic Validation
  2. Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity

Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity

  • Toxicol Lett. 2021 Oct 1;349:115-123. doi: 10.1016/j.toxlet.2021.05.013.
Ting Zhan 1 Hao Xiong 2 Jiaqi Pang 3 Weijian Zhang 4 Yongyi Ye 5 Zhengrong Liang 6 Xiaotong Huang 1 Feinan He 1 Bingquan Jian 1 Wuhui He 1 Yiming Gao 1 Xin Min 1 Yiqing Zheng 7 Haidi Yang 8
Affiliations

Affiliations

  • 1 Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 2 Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 4 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 5 School of Public Health, Sun Yat-Sen University, Guangzhou, China.
  • 6 Department of Otolaryngology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
  • 7 Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China; Department of Hearing and Speech-Language Science, Xinhua College, Guangzhou, China. Electronic address: zhengyiq@mail.sysu.edu.cn.
  • 8 Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China; Department of Hearing and Speech-Language Science, Xinhua College, Guangzhou, China. Electronic address: yanghd@mail.sysu.edu.cn.
Abstract

Cisplatin, the most widely used platinum-based Anticancer drug, often causes progressive and irreversible sensorineural hearing loss in Cancer patients. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. Nicotinamide adenine dinucleotide (NAD+), a co-substrate for the Sirtuin family and PARPs, has emerged as a potent therapeutic molecular target in various diseases. In our investigates, we observed that NAD+ level was changed in the cochlear explants of mice treated with cisplatin. Supplementation of a specific inhibitor (TES-1025) of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), a rate-limiting Enzyme of NAD+de novo synthesis pathway, promoted SIRT1 activity, increased mtDNA contents and enhanced AMPK expression, thus significantly reducing hair cells loss and deformation. The protection was blocked by EX527, a specific SIRT1 Inhibitor. Meanwhile, the use of NMN, a precursor of NAD+ salvage synthesis pathway, had shown beneficial effect on hair cell under cisplatin administration, effectively suppressing PARP1. In vivo experiments confirmed the hair cell protection of NAD+ modulators in cisplatin treated mice and zebrafish. In conclusion, we demonstrated that modulation of NAD+ biosynthesis via the de novo synthesis pathway and the salvage synthesis pathway could both prevent ototoxicity of cisplatin. These results suggested that direct modulation of cellular NAD+ levels could be a promising therapeutic approach for protection of hearing from cisplatin-induced ototoxicity.

Keywords

ACMSD; Cisplatin; NAD(+); Ototoxicity; SIRT1.

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