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CLC number: R733.72

On-line Access: 2012-11-05

Received: 2012-01-14

Revision Accepted: 2012-07-02

Crosschecked: 2012-10-15

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Journal of Zhejiang University SCIENCE B 2012 Vol.13 No.11 P.867-874

10.1631/jzus.B1200021


Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis


Author(s):  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

Affiliation(s):  Department of Hematology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; more

Corresponding email(s):   zrxz@zju.edu.cn, zrxyk10@zju.edu.cn

Key Words:  Chronic myeloid leukemia, Imatinib-resistance, Tetrandrine citrate, Bcr-Abl protein, β, -catenin protein


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. Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis[J]. Journal of Zhejiang University Science B, 2012, 13(11): 867-874.

@article{title="Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis",
author="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",
journal="Journal of Zhejiang University Science B",
volume="13",
number="11",
pages="867-874",
year="2012",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1200021"
}

%0 Journal Article
%T Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis
%A Xiao-hua Xu
%A Yi-chao Gan
%A Gen-bo Xu
%A Ting Chen
%A Hong Zhou
%A Jin-fen Tang
%A Ying Gu
%A Fei Xu
%A Ying-ying Xie
%A Xiao-ying Zhao
%A Rong-zhen Xu
%J Journal of Zhejiang University SCIENCE B
%V 13
%N 11
%P 867-874
%@ 1673-1581
%D 2012
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1200021

TY - JOUR
T1 - Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis
A1 - Xiao-hua Xu
A1 - Yi-chao Gan
A1 - Gen-bo Xu
A1 - Ting Chen
A1 - Hong Zhou
A1 - Jin-fen Tang
A1 - Ying Gu
A1 - Fei Xu
A1 - Ying-ying Xie
A1 - Xiao-ying Zhao
A1 - Rong-zhen Xu
J0 - Journal of Zhejiang University Science B
VL - 13
IS - 11
SP - 867
EP - 874
%@ 1673-1581
Y1 - 2012
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1200021


Abstract: 
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 (IC50) ranged from 1.20 to 2.97 μg/ml. In contrast, tetrandrine citrate did not affect normal blood cells under the same conditions, and IC50 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 p210Bcr-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 p210Bcr-Abl protein. RT-PCR results showed that tetrandrine treatment caused a decrease of Bcr-Abl mRNA. FCM analysis indicated that tetrandrine induced gap 1 (G1) 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 p210Bcr-Abl mRNA and β;-catenin protein.

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