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Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis.

ABSTRACT: c-Maf is a critical oncogenic transcription factor that contributes to myelomagenesis. Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf and promotes myeloma cell proliferation and survival; therefore, the USP5/c-Maf axis could be a potential target for myeloma therapy. As a concept of principle, the present study established a USP5/c-Maf-based luciferase system that was used to screen an FDA-approved drug library. It was found that mebendazole, a typical anthelmintic drug, preferentially induced apoptosis in c-Maf-expressing myeloma cells. Moreover, oral administration of mebendazole delayed the growth of human myeloma xenografts in nude mice but did not show overt toxicity. Further studies showed that the selective antimyeloma activity of mebendazole was associated with the inhibition of the USP5/c-Maf axis. Mebendazole downregulated USP5 expression and disrupted the interaction between USP5 and c-Maf, thus leading to increased levels of c-Maf ubiquitination and subsequent c-Maf degradation. Mebendazole inhibited c-Maf transcriptional activity, as confirmed by both luciferase assays and expression measurements of c-Maf downstream genes. In summary, this study identified mebendazole as a USP5/c-Maf inhibitor that could be developed as a novel antimyeloma agent.

SUBMITTER: Chen XH

PROVIDER: S-EPMC7468578 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis.

Chen Xue-Han XH Xu Yu-Jia YJ Wang Xiao-Ge XG Lin Peng P Cao Bi-Yin BY Zeng Yuan-Ying YY Wang Qi Q Zhang Zu-Bin ZB Mao Xin-Liang XL Zhang Tie T

Acta pharmacologica Sinica 20190613 12

c-Maf is a critical oncogenic transcription factor that contributes to myelomagenesis. Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf and promotes myeloma cell proliferation and survival; therefore, the USP5/c-Maf axis could be a potential target for myeloma therapy. As a concept of principle, the present study established a USP5/c-Maf-based luciferase system that was used to screen an FDA-approved drug library. It was found that mebendazole, a typical anthelmint ...[more]

PMID: 31197245

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Project description:Multiple Myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC50s from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand-breaks (DSB), evidenced by an increase in phospho-Histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53-wild type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSB and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumours also demonstrated Histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA-damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumour plasma cells to DSB, and strongly supports the use of this compound in MM patients. Experiment Overall Design: MM cells treated in vitro with Zalypsis (5 nM) were harvested at the beginning of induction of cell death (15-20% cell death as assessed by Annexin V-FITC staining). Total RNA was extracted using Trizol reagent (Life Technologies, MD, USA) and purified with RNAeasy Mini Kit (Qiagen, CA, USA). RNA integrity was verified with the Agilent 2100 Bioanalyzer (Agilent, CA, USA). Double-stranded cDNA and biotinylated cRNA were synthesized with T7-polyT primer and the BioArray RNA labeling kit (Enzo, NY, USA), respectively. The labelled RNA was then fragmented and hybridized to HG-U133 Plus 2.0 oligonucleotide arrays (Affymetrix, CA, USA), which were scanned in a Gene Array Scanner and analyzed using the DNA-Chip Analyzer software (DChip). Changes in gene expression greater than two-fold were considered significant.

Dataset Information

Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis.

Publications

Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis.

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