Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model

Riccardo Serra, Tianna Zhao, Sakibul Huq, Noah Leviton Gorelick, Joshua Casaos, Arba Cecia, Antonella Mangraviti, Charles Eberhart, Renyuan Bai, Alessandro Olivi, Henry Brem, Eric M. Jackson, Betty Tyler

Research output: Contribution to journalArticlepeer-review


Background Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of Disulfiram (DSF), an FDA-approved inhibitor of Aldehyde-Dehydrogenase (ALDH), and Copper (Cu++) in human SSH-driven and Group 3 MB. The molecular mechanisms, effect on cancer-stem-cells (CSC) and DNA damage were investigated in xenograft models. Methods The cytotoxic and anti-CSC effects of DSF/Cu++ were evaluated with clonogenic assays, flow-cytometry, immunofluorescence, western-blotting. ONS76, UW228 (SHH-driven with Tp53m), D425med, D283 and D341 (Group 3) cell-lines were used. In vivo survival and nuclear protein localization protein-4 (NPL4), Ki67, Cleaved-Caspase-3, GFAP and NeuN expression were assessed in two Group 3 MB xenografts with immunohistochemistry and western-blotting. Results Significant in vitro cytotoxicity was demonstrated at nanomolar concentrations. DSF/Cu++ induced cell-death through NPL4 accumulation in cell-nucleus and buildup of poly-ubiquitylated proteins. Flow-cytometry demonstrated a significant decrease in ALDH+, Nestin+ and CD133+ following treatment, anti-CSC effect was confirmed in vitro and in vivo. DSF/Cu++ prolonged survival, and increased nuclear NPL4 expression in vivo. Conclusions Our data suggest that this combination may serve as a novel treatment, as monotherapy or in combination with existing therapies, for aggressive subtypes of pediatric MB.

Original languageEnglish (US)
Article numbere0251957
JournalPloS one
Issue number11 November
StatePublished - Nov 2021

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model'. Together they form a unique fingerprint.

Cite this