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

Abstract

Disulfiram (DSF) is a sulphur-containing compound and has been used to treat chronic alcoholism and cancer for decades. DSF inactivates aldehyde dehydrogenase (ALDH) by modifying its cysteine residue(s). ALDH is recently identified as a cancer stem cell marker, facilitating cell self-renewal and tumour-initiating capacity. Hydrogen sulphide (H2S) as a new gasotransmitter regulates various cellular functions by the S-sulfhydration of cysteine residues in target proteins. H2S has also been shown to exhibit similar properties to DSF in the sensitization of cancer cells to chemotherapeutic agents. Here, the potential of DSF as a H2S-releasing donor under various conditions was investigated and the roles of H2S in the DSF-mediated inhibition of ALDH activity and decrease in cell viability in liver cancer cells were also examined. It was demonstrated that DSF facilitated H2S release from thiol-containing compounds, and DSF and H2S were both capable of regulating ALDH through inhibition of gene expression and enzymatic activity. The supplement of H2S sensitized human liver cancer cells (HepG2) to DSF induced reduction in cell viability. The expression of cystathionine gamma-lyase (a major H2S-generating enzyme) was lower but ALDH was higher in mouse liver cancer stem cells (Dt81Hepa1-6) in comparison with their parental cells (Hepa1-6), and H2S was able to inhibit liver cancer stem cell adhesion. In conclusion, these data provide some clues for combining with DSF and H2S for inhibition of cancer cell growth and tumour development by targeting ALDH.