Oncotarget

Research Papers:

Anti-hepatocellular carcinoma properties of the anti-alcoholism drug disulfiram discovered to enzymatically inhibit the AMPK-related kinase SNARK in vitro

Kaku Goto, Naoya Kato and Raymond T. Chung _

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Oncotarget. 2016; 7:74987-74999. https://doi.org/10.18632/oncotarget.11820

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Abstract

Kaku Goto1, Naoya Kato1, Raymond T. Chung2

1The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan

2Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA

Correspondence to:

Raymond T. Chung, email: Chung.Raymond@mgh.harvard.edu

Naoya Kato, email: kato-2im@ims.u-tokyo.ac.jp

Keywords: disulfiram, Antabuse, SNARK, NUAK2, HCC

Received: April 19, 2016    Accepted: August 24, 2016    Published: September 02, 2016

ABSTRACT

We recently described that the anti-apoptotic AMPK-related kinase, SNARK, promotes transforming growth factor (TGF)-β 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-β 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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