CLC number: R733.72
On-line Access: 2012-11-05
Received: 2012-01-14
Revision Accepted: 2012-07-02
Crosschecked: 2012-10-15
Cited: 7
Clicked: 6609
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.
[1]Barnes, D.J., Melo, J.V., 2006. Primitive, quiescent and difficult to kill: the role of non-proliferating stem cells in chronic myeloid leukemia. Cell Cycle, 5(24):2862-2866.
[2]Chen, Y., Tseng, S.H., 2010. The potential of tetrandrine against gliomas. Anticancer Agents Med. Chem., 10(7):534-542.
[3]Chen, Y., Hu, Y., Zhang, H., Peng, C., Li, S., 2009a. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat. Genet., 41(7):783-792.
[4]Chen, Y., Hu, Y., Michaels, S., Segal, D., Brown, D., Li, S., 2009b. Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia, 23(8):1446-1454.
[5]Coluccia, A.M., Vacca, A., Duñach, M., Mologni, L., Redaelli, S., Bustos, V.H., Benati, D., Pinna, L.A., Gambacorti-Passerini, C., 2007. Bcr-Abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylation. EMBO J., 26(5):1456-1466.
[6]Dierks, C., Beigi, R., Guo, G.R., Zirlik, K., Stegert, M.R., Manley, P., Trussell, C., Schmitt-Graeff, A., Landwerlin, K., Veelken, H., et al., 2008. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell, 14(3):238-249.
[7]Elrick, L.J., Jorgensen, H.G., Mountford, J.C., Holyoake, T.L., 2005. Punish the parent not the progeny. Blood, 105(5):1862-1866.
[8]Guzman, M.L., Rossi, R.M., Karnischky, L., Li, X., Peterson, D.R., Howard, D.S., Jordan, C.T., 2005. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood, 105(11):4163-4169.
[9]He, B.C., Gao, J.L., Zhang, B.Q., Luo, Q., Shi, Q., Kim, S.H., Huang, E., Gao, Y., Yang, K., Wagner, E.R., et al., 2011. Tetrandrine inhibits Wnt/β-catenin signaling and suppresses tumor growth of human colorectal cancer. Mol. Pharmacol., 79(2):211-219.
[10]Holtz, M.S., Forman, S.J., Bhatia, R., 2005. Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli. Leukemia, 19(6):1034-1041.
[11]Holyoake, T., Jiang, X., Eaves, C., Eaves, A., 1999. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood, 94(6):2056-2064.
[12]Hu, Y., Chen, Y., Douglas, L., Li, S., 2009. β-Catenin is essential for survival of leukemia stem cells in sensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia, 23(1):109-116.
[13]Konig, H., Holtz, M., Modi, H., Manley, P., Holyoake, T.L., Forman, S.J., Bhatia, R., 2008. Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors. Leukemia, 22(4):748-755.
[14]Krause, D.S., Lazarides, K., von Andrian, U.H., van Etten, R.A., 2006. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat. Med., 12(10):1175-1180.
[15]Lai, J.H., 2002. Immunomodulatory effects and mechanisms of plant alkaloid tetrandrine in autoimmune diseases. Acta Pharmacol. Sin., 23(12):1093-1101.
[16]Lee, J.H., Kang, G.H., Kim, K.C., Kim, K.M., Park, D.I., Choi, B.T., Kang, H.S., Lee, Y.T., Choi, Y.H., 2002. Tetrandrine-induced cell cycle arrest and apoptosis in A549 human lung carcinoma cells. Int. J. Oncol., 21(6):1239-1244.
[17]Li, S., Li, D., 2007. Stem cell and kinase activity-independent pathway in resistance of leukaemia to BCR-ABL kinase inhibitors. J. Cell. Mol. Med., 11(6):1251-1262.
[18]Liu, C., Gong, K., Mao, X., Li, W., 2011. Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma. Int. J. Cancer, 129(6):1519-1531.
[19]McCubrey, J.A., Steelman, L.S., Abrams, S.L., Bertrand, F.E., Ludwig, D.E., Bäsecke, J., Libra, M., Stivala, F., Milella, M., Tafuri, A., Lunghi, P., et al., 2008. Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia, 22(4):708-722.
[20]Meng, L.H., Zhang, H., Hayward, L., Takemura, H., Shao, R.G., Pommier, Y., 2004. Tetrandrine induces early G1 arrest in human colon carcinoma cells by down-regulating the activity and inducing the degradation of G1-S-specific cyclin-dependent kinases and by inducing p53 and p21Cip1. Cancer Res., 64(24):9086-9092.
[21]Ng, L.T., Chiang, L.C., Lin, Y.T., Lin, C.C., 2006. Antiproliferative and apoptotic effects of tetrandrine on different human hepatoma cell lines. Am. J. Chin. Med., 34(1):125-135.
[22]Stuart, S.A., Minami, Y., Wang, J.Y., 2009. The CML stem cell: evolution of the progenitor. Cell Cycle, 8(9):1338-1343.
[23]Wang, F.P., Wang, L., Yang, J.S., Nomura, M., Miyamoto, K., 2005. Reversal of P-glycoprotein-dependent resistance to vinblastine by newly synthesized bisbenzylisoquinoline alkaloids in mouse leukemia P388 cells. Biol. Pharm. Bull., 28(10):1979-1982.
[24]Xu, R., Dong, Q., Yu, Y., Zhao, X., Gan, X., Wu, D., Lu, Q., Xu, X., Yu, X.F., 2006. Berbamine: a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity. Leuk. Res., 30(1):17-23.
[25]Zhang, Y., Wang, C., Wang, H., Wang, K., Du, Y., Zhang, J., 2011. Combination of Tetrandrine with cisplatin enhances cytotoxicity through growth suppression and apoptosis in ovarian cancer in vitro and in vivo. Cancer Lett., 304(1):21-32.
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