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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 H<jats:sub>2<\/jats:sub>S donors, induces melanoma cell death in vitro and in vivo. Consistent with previous reports, ADT-OH inhibited I\u03baB\u0251 degradation, resulting in reduced NF-\u03baB activation and subsequent downregulation of the NF-\u03baB-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 <jats:italic>Salmonella<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41419-020-2222-9","type":"journal-article","created":{"date-parts":[[2020,1,16]],"date-time":"2020-01-16T19:06:15Z","timestamp":1579201575000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["ADT-OH, a hydrogen sulfide-releasing donor, induces apoptosis and inhibits the development of melanoma in vivo by upregulating FADD"],"prefix":"10.1038","volume":"11","author":[{"given":"Fangfang","family":"Cai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huangru","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nini","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunwen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Chun","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqin","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,16]]},"reference":[{"key":"2222_CR1","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/S0140-6736(18)31559-9","volume":"392","author":"D Schadendorf","year":"2018","unstructured":"Schadendorf, D. et al. 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