Anticancer Effects of New Disulfiram Analogs

Disulfiram (DSF), an irreversible aldehyde dehydrogenase 2 (ALDH2) inhibitor, is an U.S. Food and Drug Administration (FDA)-approved drug for the treatment of chronic alcoholism. Recent studies have reported an interesting antitumor activity of DSF against a wide range of human malignancies, while a growing number of ongoing and completed clinical trials have provided evidence supporting the repurposing of DSF as an anticancer treatment. Nevertheless, despite its current clinical indications and potential future therapeutic applications for treating various diseases, DSF is associated with serious side effects attributed to the inhibition of ALDH2. We have recently synthesized DSF analogs (2a-v) with limited inhibition of ALDH2. Here, we report the anticancer activity of these molecules by highlighting their effects on cell signaling in Jurkat cells. DSF and two DSF analogs, 2g and 2r, all stimulated apoptotic signaling pathways, although the 2g analog activated more apoptosis-related genes and induced higher levels of apoptosis in vitro. Differential gene expression data suggested that compounds 2g and 2r specifically reprogram target cells to downregulate pathways related to cell growth and division, while upregulating pathways related to apoptosis or differentiation. Interestingly, both compounds 2g and 2r had more differentially expressed genes related to DNA damage pathways (including those related to apoptosis) when compared to DSF, which may offer insights into their mechanisms of action.