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

Highlights: • Disulfiram facilitates H₂S release from thiol-containing compounds. • Disulfiram induces CSE expression and H₂S generation in human liver cancer cells. • H₂S sensitizes liver cancer cells to disulfiram-inhibited cell viability. • H₂S inhibits ALDH activity and liver cancer stem cell adhesion. Disulfiram (DSF), a sulfur-containing compound, has been used to treat chronic alcoholism and cancer for decades by inactivating aldehyde dehydrogenase (ALDH). Hydrogen sulfide (H₂S) is a new gasotransmitter and regulates various cellular functions by S-sulfhydrating cysteine in the target proteins. H₂S exhibits similar properties to DSF in the sensitization of cancer cells. The interaction of DSF and H₂S on ALDH activity and liver cancer cell survival are not clear. Here 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-inhibited 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 point to the potential of combining DSF and H₂S for inhibition of cancer cell growth and tumor development by targeting ALDH.