Mechanism of cystathionine-β-synthase inhibition by disulfiram: The role of bis(N,N-diethyldithiocarbamate)-copper(II)

Overproduction of hydrogen sulfide, generated by cystathionine β-synthase, disrupts brain wave patterns and contributes to neurobehavioral dysfunction in a rat model of down syndrome

“…Our working hypothesis [ 6 ] is that this bioenergetic imbalance makes DS individuals viable, but the energetic defects may manifest, for instance, in reduced exercise tolerance, as well as – potentially – in altered neurological and/or muscle function [ 4 , 6 ]. Recent in vivo studies have, in fact, indicated that forced overexpression of CBS in the mouse brain, on its own, can produce neurobehavioral defects associated with DS, and preliminary pharmacological studies with disulfiram, a multifunctional compound – which, among other pharmacological effects, acts as a CBS inhibitor in vivo [ 9 , 10 ] –, improves neurological function in a mouse model of DS [ 10 ].…”

“…We would like to emphasize that the beneficial neurobehavioral effects in murine DS models have previously been reported with genetic normalization of CBS, as well as effects with disulfiram (which has CBS inhibitory effects in vivo, although it also has additional pharmacological actions as well) [ 9 , 10 ]. Thus, based on the results of the current study – taken together with multiple independent studies implicating the CBS/H 2 S pathway in the pathogenesis of DS [ [3] , [4] , [5] , [6] ] – indicate that H 2 S overproduction is a likely pathogenetic factor in DS and CBS inhibition should be considered as a potential future experimental therapeutic target to improve the neurocognitive function associated with DS.…”

“…Since this inhibition is biochemically reversible, pharmacological inhibition of CBS has the potential to improve bioenergetic (and, thereby, overall cellular functional) status, even in established DS. Indeed, in in-vitro studies, using various pharmacological CBS inhibitors, including the prototypical inhibitor aminooxyacetate (AOAA), were found to restore mitochondrial electron transport and ATP generation in human DS fibroblasts [ 8 , 9 ]. In an independent line of studies, CBS overexpression was shown to phenocopy the DS-like neurocognitive deficits in mice, while genetic deletion of CBS in DS mice has been shown to improve neurobehavioral function [ 10 ].…”

The interaction of disulfiram and H2S metabolism in inhibition of aldehyde dehydrogenase activity and liver cancer cell growth

“…showed that DSF via its metabolite DDC-Cu inhibited CBS activity and H2S levels in colon cancer cells 94 . The inconsistency may be due to the differences in cell types and/or the substrate/cofactors used.…”

Repurposing Disulfiram for Targeting of Glioblastoma Stem Cells: An In Vitro Study

“…This disulfiram/Cu 2+ -mediated impairment of redox homeostasis [ 33 ] is most probably the reason for the observed pleiotropic actions of disulfiram. Besides blockage of ALDH isoforms, disulfiram/Cu 2+ reportedly modulate among others the proteasome [ 42 ], DNA-methyltransferases [ 43 ] including the O6-methylguanin-DNA-methyltransferase [ 44 ], the cystathionine-β-synthase [ 45 ], matrix metalloproteinases-2 and -8 [ 46 ], caspases [ 47 ], the EGFR/c-Src/VEGF-pathway [ 48 ], the NF-κB and TGF-β pathway [ 6 ], cell-matrix adhesion [ 49 ], lysosomal membrane integrity [ 50 ], immunogenic cell death [ 3 ], immunosuppression [ 2 ], as well as sensitivity to chemo- (e.g., [ 51 ]) and radio-therapy (e.g., [ 10 ]).…”