Tliptolide induces caspase-dependent cell death mediated via the mitochondfial pathway in leukemic cells

被引:167
作者
Carter, Bing Z.
Mak, Duncan H.
Schober, Wendy D.
McQueen, Teresa
Harris, David
Estrov, Zeev
Evans, Randall L.
Andreeff, Michael
机构
[1] Univ Texas, MD Anderson Canc Ctr, Sect Mol Hematol & Therapy, Dept Blood & Marrow Transplantat, Houston, TX 77030 USA
[2] Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
关键词
D O I
10.1182/blood-2005-09-3898
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Triptolide, a diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook.f, has shown antitumor activities in a broad range of solid tumors. Here, we examined its effects on leukemic cells and found that, at 100 nM or less, it potently induced apoptosis in various leukemic cell lines and primary acute myeloid leukemia (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-X-L levels. Bcl-2 overexpression suppressed triptolide-induced apoptosis. Further, triptolide induced loss of the mitochondrial membrane potential and cytochrome C release. Caspase-9 knock-out cells were resistant, while caspase-8-deficient cells were sensitive to triptolide, suggesting criticality of the mitochondrial but hot the death receptor pathway for triptolide-induced apoptosis. Triptolide also enhanced cell death induced by other anticancer 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 antileukemic activity of triptolide in vitro warrants further investigation of this compound for the treatment of leukemias and other malignancies.
引用
收藏
页码:630 / 637
页数:8
相关论文
共 54 条
[1]   Survivin and apoptosis control [J].
Altieri, DC .
ADVANCES IN CANCER RESEARCH, VOL 88, 2003, 88 :31-52
[2]  
Altieri DC, 1999, LAB INVEST, V79, P1327
[3]   Differential response of human acute myeloid leukemia cells to gemtuzumab ozogamicin in vitro: role of Chk1 and Chk2 phosphorylation and caspase 3 [J].
Amico, D ;
Barbui, AM ;
Erba, E ;
Rambaldi, A ;
Introna, M ;
Golay, J .
BLOOD, 2003, 101 (11) :4589-4597
[4]  
BERAN M, 1993, CANCER RES, V53, P3603
[5]   Pretreatment with DNA-damaging agents permits selective killing of checkpoint-deficient cells by microtubule-active drugs [J].
Blagosklonny, MV ;
Robey, R ;
Bates, S ;
Fojo, T .
JOURNAL OF CLINICAL INVESTIGATION, 2000, 105 (04) :533-539
[6]   Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis [J].
Carter, BZ ;
Kornblau, SM ;
Tsao, T ;
Wang, RY ;
Schober, WD ;
Milella, M ;
Sung, HG ;
Reed, JC ;
Andreeff, M .
BLOOD, 2003, 102 (12) :4179-4186
[7]   Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia [J].
Carter, BZ ;
Milella, M ;
Tsao, T ;
McQueen, T ;
Schober, WD ;
Hu, W ;
Dean, NM ;
Steelman, L ;
McCubrey, JA ;
Andreeff, M .
LEUKEMIA, 2003, 17 (11) :2081-2089
[8]   Triptolide and chemotherapy cooperate in tumor cell apoptosis - A role for the p53 pathway [J].
Chang, WT ;
Kang, JJ ;
Lee, KY ;
Wei, K ;
Anderson, E ;
Gotmare, S ;
Ross, JA ;
Rosen, GD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (03) :2221-2227
[9]   Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium Wilfordii Hook F [J].
Chen, BJ .
LEUKEMIA & LYMPHOMA, 2001, 42 (03) :253-265
[10]   Immunosuppressant PG490 (triptolide) induces apoptosis through the activation of caspase-3 and down-regulation of XIAP in U937 cells [J].
Choi, YJ ;
Kim, TG ;
Kim, YH ;
Lee, SH ;
Kwon, YK ;
Suh, SI ;
Park, JW ;
Kwon, TK .
BIOCHEMICAL PHARMACOLOGY, 2003, 66 (02) :273-280