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Disulfiram/copper targets stem cell‐like ALDH + population of multiple myeloma by inhibition of ALDH1A1 and Hedgehog pathway
Author(s) -
Jin Na,
Zhu Xiaojian,
Cheng Fanjun,
Zhang Liling
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26885
Subject(s) - aldehyde dehydrogenase , homeobox protein nanog , disulfiram , stem cell , cancer research , cancer stem cell , gli1 , chemistry , in vivo , lin28 , side population , biology , microbiology and biotechnology , sox2 , transcription factor , hedgehog signaling pathway , biochemistry , induced pluripotent stem cell , enzyme , signal transduction , embryonic stem cell , gene
Multiple myeloma stem cells (MMSCs) have been considered as the major cause resulting in relapse. Eradicating MMSCs may be an effective strategy to improve the outcome of multiple myeloma (MM). Increased activity of aldehyde dehydrogenase (ALDH) has been found in MMSCs, but whether inhibiting ALDH activity can eliminate MMSCs remains unknown. Disulfiram (DS) has been reported as an inhibitor of ALDH, and increasing studies showed it has anti‐cancer effects in a copper (Cu)‐dependent manner. In this study, we isolated ALDH + cells of MM by Aldefluor assay and demonstrated they possessed tumorigenesis capacities in vitro and in vivo. Next, we investigated the effects of DS with or without Cu on suppressing the stemness of MM both in vitro and in vivo. We found that DS/Cu eliminated the stem cell‐like ALDH + cells. Furthermore, we demonstrated that DS/Cu inhibited the expression of stem cell transcription factors NANOG and OCT4, and abolished the clonogenicity of MM. We also showed that DS/Cu reduced the tumor growth and inhibited stemness of MM in xenograft model. We further found the specific target of DS/Cu is ALDH1A1 and DS/Cu inhibited the Hedgehog (Hh) pathway transcription factors Gli1 and Gli2 regulated by ALDH1A1 at least in part. Our data suggest that DS/Cu can inhibit the ALDH + stem cell‐like cells through ALDH1A1 and Hh pathway, which may be a promising therapeutic agent in eradicating stem cell‐like cells of MM.