Research Papers:

Novel therapeutic features of disulfiram against hepatocellular carcinoma cells with inhibitory effects on a disintegrin and metalloproteinase 10

Kaku Goto _, Jun Arai, Anthony Stephanou and Naoya Kato

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2018; 9:18821-18831. https://doi.org/10.18632/oncotarget.24568

Metrics: PDF 1868 views  |   HTML 2647 views  |   ?  


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

Correspondence to:

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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 24568