2. Academic Validation
  3. 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.
PMID: 34089817 DOI: 10.1016/j.toxlet.2021.05.013
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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