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Blood, 15 July 2006, Vol. 108, No. 2, pp. 630-637. Prepublished online as a Blood First Edition Paper on March 23, 2006; DOI 10.1182/blood-2005-09-3898. This Article Full Text (PDF) All Versions of this Article: 2005-09-3898v1 108/2/630    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Carter, B. Z Articles by Andreeff, M. Search for Related Content PubMed PubMed Citation Articles by Carter, B. Z Articles by Andreeff, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 29, 2005 Accepted February 12, 2006 Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells Bing Z Carter, Duncan H Mak, Wendy D Schober, Teresa McQueen, David Harris, Zeev Estrov, Randall L Evans, and Michael Andreeff* Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA; Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA * Corresponding author; email: mandreef{at}mdanderson.org. Triptolide, a diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook.f, has shown anti-tumor activities in a broad range of solid tumors. Here we examined its effects on leukemic cells and found that, at 100nM, it potently induced apoptosis in various leukemic cell lines and primary AML blasts. We then attempted to identify its mechanisms of action. Triptolide induced caspase-dependent cell death accompanied by a significant decrease in XIAP levels. Forced XIAP overexpression attenuated triptolide-induced cell death. Triptolide also decreased Mcl-1, but not Bcl-2 and Bcl-XL levels. Bcl-2 overexpression suppressed triptolide-induced apoptosis. Further, triptolide induced loss of the mitochondrial membrane potential and cytochrome C release. Caspase-9-knockout cells were resistant, while caspase-8-deficient cells were sensitive to triptolide suggesting criticality of the mitochondrial, but not the death receptor pathway for triptolide-induced apoptosis. Triptolide also enhanced cell death induced by other anti-cancer agents. Collectively, our results demonstrate that triptolide decreases XIAP and potently induces caspase-dependent apoptosis in leukemic cells mediated through the mitochondrial pathway at low nanomolar concentrations. The potent anti-leukemic activity of triptolide in vitro warrants further investigation of this compound for the treatment of leukemias and other malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Vispe, L. DeVries, L. Creancier, J. Besse, S. Breand, D. J. Hobson, J. Q. Svejstrup, J.-P. Annereau, D. Cussac, C. Dumontet, et al. Triptolide is an inhibitor of RNA polymerase I and II-dependent transcription leading predominantly to down-regulation of short-lived mRNA Mol. Cancer Ther., October 1, 2009; 8(10): 2780 - 2790. [Abstract] [Full Text] [PDF] D. H. Mak, W. D. Schober, W. Chen, M. Konopleva, J. Cortes, H. M. Kantarjian, M. Andreeff, and B. Z. Carter Triptolide induces cell death independent of cellular responses to imatinib in blast crisis chronic myelogenous leukemia cells including quiescent CD34+ primitive progenitor cells Mol. Cancer Ther., September 1, 2009; 8(9): 2509 - 2516. [Abstract] [Full Text] [PDF] S Ghavami, M Hashemi, S R Ande, B Yeganeh, W Xiao, M Eshraghi, C J Bus, K Kadkhoda, E Wiechec, A J Halayko, et al. Apoptosis and cancer: mutations within caspase genes J. Med. Genet., August 1, 2009; 46(8): 497 - 510. [Abstract] [Full Text] [PDF] X. Shi, Y. Jin, C. Cheng, H. Zhang, W. Zou, Q. Zheng, Z. Lu, Q. Chen, Y. Lai, and J. Pan Triptolide Inhibits Bcr-Abl Transcription and Induces Apoptosis in STI571-resistant Chronic Myelogenous Leukemia Cells Harboring T315I Mutation Clin. Cancer Res., March 1, 2009; 15(5): 1686 - 1697. [Abstract] [Full Text] [PDF] S. J. Leuenroth and C. M. Crews Triptolide-Induced Transcriptional Arrest Is Associated with Changes in Nuclear Substructure Cancer Res., July 1, 2008; 68(13): 5257 - 5266. [Abstract] [Full Text] [PDF] B. Z. Carter, D. H. Mak, W. D. Schober, M. F. Dietrich, C. Pinilla, L. T. Vassilev, J. C. Reed, and M. Andreeff Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5 Blood, April 1, 2008; 111(7): 3742 - 3750. [Abstract] [Full Text] [PDF] P. A. Phillips, V. Dudeja, J. A. McCarroll, D. Borja-Cacho, R. K. Dawra, W. E. Grizzle, S. M. Vickers, and A. K. Saluja Triptolide Induces Pancreatic Cancer Cell Death via Inhibition of Heat Shock Protein 70 Cancer Res., October 1, 2007; 67(19): 9407 - 9416. [Abstract] [Full Text] [PDF] W. Wang, S. Yang, Y. Su, Z. Xiao, C. Wang, X. Li, L. Lin, B. M. Fenton, S. F. Paoni, I. Ding, et al. Enhanced Antitumor Effect of Combined Triptolide and Ionizing Radiation Clin. Cancer Res., August 15, 2007; 13(16): 4891 - 4899. [Abstract] [Full Text] [PDF] S. J. Leuenroth, D. Okuhara, J. D. Shotwell, G. S. Markowitz, Z. Yu, S. Somlo, and C. M. Crews Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease PNAS, March 13, 2007; 104(11): 4389 - 4394. [Abstract] [Full Text] [PDF]

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