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

Disulfiram (DSF), a sulfur-containing compound, has been used to treat chronic alcoholism and cancer for decades by inactivating aldehyde dehydrogenase (ALDH). Hydrogen sulfide (HS) is a new gasotransmitter and regulates various cellular functions by S-sulfhydrating cysteine in the target proteins. HS exhibits similar properties to DSF in the sensitization of cancer cells. The interaction of DSF and HS on ALDH activity and liver cancer cell survival are not clear. Here it was demonstrated that DSF facilitated HS release from thiol-containing compounds, and DSF and HS were both capable of regulating ALDH through inhibition of gene expression and enzymatic activity. The supplement of HS sensitized human liver cancer cells (HepG2) to DSF-inhibited cell viability. The expression of cystathionine gamma-lyase (a major HS-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 HS was able to inhibit liver cancer stem cell adhesion. In conclusion, these data point to the potential of combining DSF and HS for inhibition of cancer cell growth and tumor development by targeting ALDH.