Document Detail


Dihydroartemisinin accelerates c-MYC oncoprotein degradation and induces apoptosis in c-MYC-overexpressing tumor cells.
MedLine Citation:
PMID:  20206143     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Artemisinin and its derivatives (ARTs) are effective antimalarial drugs and also possess profound anticancer activity. However, the mechanism accounted for its distinctive activity in tumor cells remains unelucidated. We computed Pair wise Pearson correlation coefficients to identify genes that show significant correlation with ARTs activity in NCI-55 cell lines using data obtained from studies with HG-U133A Affymetrix chip. We found c-myc is one of the genes that showed the highest positive correlation coefficients among the probe sets analyzed (r=0.585, P<0.001). Dihydroartemisinin (DHA), the main active metabolite of ARTs, induced significant apoptosis in HL-60 and HCT116 cells that express high levels of c-MYC. Stable knockdown of c-myc abrogated DHA-induced apoptosis in HCT116 cells. Conversely, forced expression of c-myc in NIH3T3 cells sensitized these cells to DHA-induced apoptosis. Interestingly, DHA irreversibly down-regulated the protein level of c-MYC in DHA-sensitive HCT116 cells, which is consistent to persistent G1 phase arrest induced by DHA. Further studies demonstrated that DHA accelerated the degradation of c-MYC protein and this process was blocked by pretreatment with the proteasome inhibitor MG-132 or GSK 3beta inhibitor LiCl in HCT116 cells. Taken together, ARTs might be useful in the treatment of c-MYC-overexpressing tumors. We also suggest that c-MYC may potentially be a biomarker candidate for prediction of the antitumor efficacies of ARTs.
Authors:
Jin-Jian Lu; Ling-Hua Meng; Uma T Shankavaram; Cai-Hua Zhu; Lin-Jiang Tong; Guang Chen; Li-Ping Lin; John N Weinstein; Jian Ding
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-03
Journal Detail:
Title:  Biochemical pharmacology     Volume:  80     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-04-27     Completed Date:  2010-05-20     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  22-30     Citation Subset:  IM    
Copyright Information:
(c) 2010 Elsevier Inc. All rights reserved.
Affiliation:
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Rd., Shanghai 201203, PR China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antimalarials / pharmacology*
Apoptosis / drug effects*
Artemisinins / pharmacology*
Cell Line, Tumor
Cysteine Proteinase Inhibitors / pharmacology
Down-Regulation / drug effects
G1 Phase / drug effects
Glycogen Synthase Kinase 3 / antagonists & inhibitors
HCT116 Cells
HL-60 Cells
Humans
Leupeptins / pharmacology
Lithium Chloride / pharmacology
Mice
NIH 3T3 Cells
Proto-Oncogene Proteins c-myc / antagonists & inhibitors,  metabolism*
Chemical
Reg. No./Substance:
0/Antimalarials; 0/Artemisinins; 0/Cysteine Proteinase Inhibitors; 0/Leupeptins; 0/Proto-Oncogene Proteins c-myc; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 71939-50-9/dihydroquinghaosu; 7447-41-8/Lithium Chloride; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3

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