Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 426, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2021.115642
Keywords
Cystathionine gamma-lyase; Disulfiram; Aldehyde dehydrogenase; Liver cancer stem cells; H2S
Categories
Funding
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2016-04051]
- Heart and Stroke Foundation of Canada [G180022098]
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Disulfiram and hydrogen sulfide can sensitize liver cancer cells by inhibiting ALDH activity, and H2S can also inhibit the adhesion of liver cancer stem cells. The combination of DSF and H2S shows potential in inhibiting cancer cell growth and tumor development by targeting ALDH.
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.
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