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Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis.
MedLine Citation:
PMID:  23125079     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Objective: To evaluate the effects of tetrandrine citrate, a novel tetrandrine salt with high water solubility, on the growth of imatinib (IM)-resistant chronic myeloid leukemia (CML) in vitro and in vivo, and reveal action molecular mechanisms. Methods: Cell viability in vitro was measured using methyl thiazolyl tetrazolium (MTT) assay. CML cell growth in vivo was assessed using a xenograft model in nude mice. Bcr-Abl and β-catenin protein levels were determined using Western blotting. Bcr-Abl messenger RNA (mRNA) was measured by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry (FCM) was used to determine cell cycle status. Results: Tetrandrine citrate inhibited the growth of IM-resistant K562 cells, primary leukemia cells, and primitive CD34(+) leukemia cells, and their inhibition concentration that inhibited 50% of target cells (IC(50)) ranged from 1.20 to 2.97 μg/ml. In contrast, tetrandrine citrate did not affect normal blood cells under the same conditions, and IC(50) values were about 10.12-13.11 μg/ml. Oral administration of tetrandrine citrate caused complete regression of IM-resistant K562 xenografts in nude mice without overt toxicity. Western blot results revealed that treatment of IM-resistant K562 cells with tetrandrine citrate resulted in a significant decrease of both p210(Bcr-Abl) and β-catenin proteins, but IM did not affect the Bcr-Abl protein levels. Proteasome inhibitor, MG132, did not prevent tetrandrine-mediated decrease of the p210(Bcr-Abl) protein. RT-PCR results showed that tetrandrine treatment caused a decrease of Bcr-Abl mRNA. FCM analysis indicated that tetrandrine induced gap 1 (G(1)) arrest in CML cells. Conclusions: Tetrandrine citrate is a novel orally active tetrandrine salt with potent anti-tumor activity against IM-resistant K562 cells and CML cells. Tetrandrine citrate-induced growth inhibition of leukemia cells may be involved in the depletion of p210(Bcr-Abl) mRNA and β-catenin protein.
Authors:
Xiao-Hua Xu; Yi-Chao Gan; Gen-Bo Xu; Ting Chen; Hong Zhou; Jin-Fen Tang; Ying Gu; Fei Xu; Ying-Ying Xie; Xiao-Ying Zhao; Rong-Zhen Xu
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of Zhejiang University. Science. B     Volume:  13     ISSN:  1862-1783     ISO Abbreviation:  J Zhejiang Univ Sci B     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-05     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101236535     Medline TA:  J Zhejiang Univ Sci B     Country:  China    
Other Details:
Languages:  eng     Pagination:  867-74     Citation Subset:  IM    
Affiliation:
Department of Hematology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Cancer Institute, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
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