Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada; Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada.
Cardiovascular and Metabolic Research Unit, Laurentian University, Sudbury, Canada; Department of Biology, Laurentian University, Sudbury, Canada.
Toxicol Appl Pharmacol. 2021 Sep 1;426:115642. doi: 10.1016/j.taap.2021.115642. Epub 2021 Jul 6.
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.
二硫苏糖醇（DSF）是一种含硫化合物，几十年来一直被用于通过使醛脱氢酶（ALDH）失活来治疗慢性酗酒和癌症。硫化氢（HS）是一种新的气体递质，通过在靶蛋白中的半胱氨酸上进行 S-硫代修饰来调节各种细胞功能。HS 在癌细胞的敏化方面表现出与 DSF 相似的特性。DSF 和 HS 对 ALDH 活性和肝癌细胞存活的相互作用尚不清楚。本研究表明，DSF 促进含巯基化合物释放 HS，DSF 和 HS 均可通过抑制基因表达和酶活性来调节 ALDH。HS 的补充使人类肝癌细胞（HepG2）对 DSF 抑制细胞活力更加敏感。与亲本细胞（Hepa1-6）相比，在小鼠肝癌干细胞（Dt81Hepa1-6）中胱硫醚γ-裂解酶（一种主要的 HS 生成酶）的表达较低，但 ALDH 较高，HS 能够抑制肝癌干细胞的黏附。总之，这些数据表明，通过靶向 ALDH，联合使用 DSF 和 HS 有可能抑制癌细胞生长和肿瘤发展。
