Journal
ONCOTARGET
Volume 7, Issue 46, Pages 74987-74999Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.11820
Keywords
disulfiram; Antabuse; SNARK; NUAK2; HCC
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology in Japan [24390184]
- Japan Agency for Medical Research and Development [15fk0310009h0004]
- Japan Society for the Promotion of Science [15K19106]
- Grants-in-Aid for Scientific Research [15K19106, 24390184] Funding Source: KAKEN
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We recently described that the anti-apoptotic AMPK-related kinase, SNARK, promotes transforming growth factor (TGF)-beta signaling in hepatocellular carcinoma (HCC) cells, as a potentially new therapeutic target. Here we explored FDA-approved drugs inhibiting the enzymatic activity of SNARK, using an in vitro luminescence kinase assay system. Interestingly, the long-used anti-alcoholism drug disulfiram (DSF), also known as Antabuse, emerged as the top hit. Enzymatic kinetics analyses revealed that DSF inhibited SNARK kinase activity in a noncompetitive manner to ATP or phosphosubstrates. Comparative in vitro analyses of DSF analogs indicated the significance of the disulfide bond-based molecular integrity for the kinase inhibition. DSF suppressed SNARK-promoted TGF-beta signaling and demonstrated anti-HCC effects. The chemical and enzymatic findings herein reveal novel pharmacological effects of and use for DSF and its derivatives, and could be conducive to prevention and inhibition of liver fibrosis and HCC.
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