Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma

PloS One
Hirofumi YoshinoMasayuki Nakagawa

Abstract

The alcohol-abuse drug disulfiram has antitumor effects against diverse cancer types via inhibition of the ubiquitin-proteasome protein nuclear protein localization protein 4 (NPL4). However, the antitumor effects of NPL4 and disulfiram in clear cell renal cell carcinoma (ccRCC) are unclear. Here, we evaluated the therapeutic potential of targeting the ubiquitin-proteasome pathway using disulfiram and RNA interference and investigated the mechanisms underlying disulfiram in ccRCC. According to data from The Cancer Genome Atlas, NPL4 mRNA expression was significantly upregulated in clinical ccRCC samples compared with that in normal kidney samples, and patients with high NPL4 expression had poor overall survival compared with patients with low NPL4 expression. Disulfiram and NPL4 siRNA inhibited ccRCC cell proliferation in vitro, and disulfiram inhibited ccRCC tumor growth in a xenograft model. Synergistic antiproliferative effects were observed for combination treatment with disulfiram and sunitinib in vitro and in vivo. In RCC cells from mice treated with disulfiram and/or sunitinib, several genes associated with serine biosynthesis and aldose reductase were downregulated in cells treated with disulfiram or sunitinib alone and...Continue Reading

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Citations

Jan 12, 2021·Cancer Chemotherapy and Pharmacology·Chen LuXiao Zhang
Jul 3, 2021·Current Oncology·Denisa Weiser Drozdkova, Katerina Smesny Trtkova

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Methods Mentioned

BETA
PCR
transfection
flow cytometry
xenograft
xenografts
RNA-seq

Software Mentioned

CellQuest
Expert Stat View

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