Document Detail


Nontoxic-dose of Deguelin Induce NPMc+ AML Cell differentiation by Selectively Targeting Mt NPM1/SIRT1 Instead of HDAC1/3.
MedLine Citation:
PMID:  25348016     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
AML with Mt NPM1 has relatively good responses to induction therapy. However, a proportion of NPMc+ AML cells cannot be cleared by conventional treatments. Therefore, we determined the therapeutic efficacy of deguelin that has demonstrated extensive biological activity with low toxicity. We previously reported that deguelin selectively reduces Mt NPM1, as well as induces differentiation and potentiates apoptosis in NPMc+ AML cells. Nevertheless, little information is available regarding the mechanism of deguelin-induced differentiation. Here, we investigated the role of deguelin in the induction of NPMc+ AML cell differentiation. Deguelin at the nontoxic concentration of 2 µM strongly inhibited cell growth but reduced apoptosis in OCI-AML3 cells carrying Mt NPM1, whereas the antiproliferative effect was minimal in OCIM2 cells harboring Wt NPM1. Compared with OCIM2 cells that showed no response, deguelin-treated OCI-AML3 cells exhibited the morphological features of granulocytic/monocytic differentiation, increased expression of differentiation antigens, and a nitroblue tetrazolium reduction activity. Induction of differentiation was associated with downregulation of Mt NPM1 and SIRT1, but not Wt NPM1, which was accompanied by an increase in CEBPβ and G-CSFR expression, and further confirmed by sh-Mt NPM1 and sh-SIRT1. sh-Mt NPM1 treatment reduced SIRT1 expression, but did not change HDAC1/3 levels, suggesting that the decline of SIRT1 was partially accountable for the deguelin-induced, Mt-NPM1-related differentiation. Moreover, Mt NPM1 overexpression blocked deguelin-induced cell differentiation. Lastly, we showed that deguelin reduced the expression of Mt NPM1 via the ubiquitin-proteasome pathway. Taken together, our results suggest that deguelin may be a therapeutic candidate for NPMc+ AML.
Authors:
YouPing Wang; Sha Yi; Lu Wen; Ben Ping Zhang; Zichu Zhao; Jing Yu Hu; Fei Zhao; Jing He; Jun Fang; Chun Zhang; Guohui Cui; Yan Chen
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-10-28
Journal Detail:
Title:  Current cancer drug targets     Volume:  -     ISSN:  1873-5576     ISO Abbreviation:  Curr Cancer Drug Targets     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-28     Completed Date:  -     Revised Date:  2014-10-29    
Medline Journal Info:
Nlm Unique ID:  101094211     Medline TA:  Curr Cancer Drug Targets     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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