Novel therapeutic features of disulfiram against hepatocellular carcinoma cells with inhibitory effects on a disintegrin and metalloproteinase 10
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Kaku Goto1,2, Jun Arai1,3, Anthony Stephanou1 and Naoya Kato1,4
1The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
2Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272-8516, Japan
3Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo 142-8555, Japan
4Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
Kaku Goto, email: [email protected]
Naoya Kato, email: [email protected]
Keywords: disulfiram; antabuse; HCC; ADAM10; MICA
Received: October 05, 2017 Accepted: February 24, 2018 Published: April 10, 2018
Our previous genome-wide association study identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) as a susceptibility gene for hepatitis C virus-induced hepatocellular carcinoma (HCC). We subsequently proved that pharmacological restoration of membrane-bound MICA in HCC cells boosted natural killer cell-mediated anti-cancer effects, confirming that a MICA sheddase, a disintegrin and metalloproteinase 10 (ADAM10), is a therapeutic target. We here searched for approved drugs with inhibitory effects on ADAM10 in vitro, and the anti-alcoholism agent, disulfiram, was identified. Disulfiram elevated membrane-bound MICA levels and reduced production of soluble MICA, an immunological decoy, while simultaneously not having unfavorable off-target effects on natural killer cells and normal human hepatocytes. Functional analyses indicated a mode of non-zinc-binding inhibition of ADAM10 by disulfiram, which also suppressed HCC cell migration. These effects of disulfiram against HCC are expected to further the development of novel therapeutic regimens.
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