Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells.
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 not 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.
Carter
Bing Z
BZ
Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas, MD Anderson Cancer Center, Houston, 77030, USA.
Mak
Duncan H
DH
Schober
Wendy D
WD
McQueen
Teresa
T
Harris
David
D
Estrov
Zeev
Z
Evans
Randall L
RL
Andreeff
Michael
M
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000187:drug effects; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000032:analysis / Q000187:drug effects / Q000494:pharmacology
D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C001899:triptolide; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases