ADT-OH, a hydrogen sulfide-releasing donor, induces apoptosis and inhibits the development of melanoma in vivo by upregulating FADD

  • Cell Death Dis. 2020 Jan 16;11(1):33. doi: 10.1038/s41419-020-2222-9.
Fangfang Cai  1 ,  Huangru Xu  1 ,  Nini Cao  1 ,  Xiangyu Zhang  1 ,  Jia Liu  1 ,  Yanyan Lu  1 ,  Jia Chen  1 ,  Yunwen Yang  1 ,  Jian Cheng  2 ,  Zi-Chun Hua  3  4 ,  Hongqin Zhuang  5
Affiliations
  • 1. The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.
  • 2. Institute of Neuroscience, Soochow University, Suzhou, China. [email protected].
  • 3. The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China. [email protected].
  • 4. Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou, 213164, China. [email protected].
  • 5. The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China. [email protected].
PMID: 31949127 DOI: 10.1038/s41419-020-2222-9
Abstract

Hydrogen sulfide (H2S) is now widely considered the third endogenous gasotransmitter and plays critical roles in Cancer biological processes. In this study, we demonstrate that 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), the most widely used moiety for synthesising slow-releasing H2S donors, induces melanoma cell death in vitro and in vivo. Consistent with previous reports, ADT-OH inhibited IκBɑ degradation, resulting in reduced NF-κB activation and subsequent downregulation of the NF-κB-targeted anti-apoptotic proteins XIAP and Bcl-2. More importantly, we found that ADT-OH suppressed the ubiquitin-induced degradation of FADD by downregulating the expression of MKRN1, an E3 ubiquitin Ligase of FADD. In addition, ADT-OH had no significant therapeutic effect on FADD-knockout B16F0 cells or FADD-knockdown A375 cells. Based on these findings, we evaluated the combined effects of ADT-OH treatment and FADD overexpression on melanoma cell death in vivo using a mouse xenograft model. As expected, tumour-specific delivery of FADD through a recombinant Salmonella strain, VNP-FADD, combined with low-dose ADT-OH treatment significantly inhibited tumour growth and induced Cancer cell Apoptosis. Taken together, our data suggest that ADT-OH is a promising Cancer therapeutic drug that warrants further investigation into its potential clinical applications.

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