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

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 I?B? degradation, resulting in reduced NF-?B activation and subsequent downregulation of the NF-?B-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.

SUBMITTER: Cai F 

PROVIDER: S-EPMC6965651 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature