Novel Therapeutic Features of Disulfiram Against Hepatocellular Carcinoma Cells with Inhibitory Effects on a Disintegrin and Metalloproteinase 10

Overview

Journal Oncotarget

Specialty Oncology

Date 2018 May 4

PMID 29721164

Citations 15

Authors

Kaku Goto

Jun Arai

Anthony Stephanou

Naoya Kato

Affiliations

Soon will be listed here.

Abstract

Our previous genome-wide association study identified the anti-tumor ligand MHC class I polypeptide-related sequence A () 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 , 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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