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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3742-3750.
Prepublished online as a Blood First Edition Paper on January 10, 2008; DOI 10.1182/blood-2007-05-091504.
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Submitted May 31, 2007
Accepted December 3, 2007
Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5
Bing Z Carter, Duncan H Mak, Wendy D Schober, Martin F Dietrich, Clemencia Pinilla, Lyubomir T Vassilev, John C Reed, and Michael Andreeff*
Stem Cell Transplantation - Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Department of Immunology, Torrey Pines Institute for Molecular Studies, La Jolla, CA, United States
Department of Research, Roche Pharmaceuticals, Nutley, NJ, United States
Burnham Institute for Medical Research, LaJolla, CA, United States
* Corresponding author; email: mandreef{at}mdanderson.org.
Acute myeloid leukemia (AML) cells are relatively resistant to TRAIL. We previously reported that triptolide, a potent anticancer agent from a Chinese herb, decreases XIAP in leukemic cells. We evaluated the combination of triptolide and TRAIL and found synergistic promotion of apoptosis in AML cells. XIAP-overexpressing U937 cells (U937XIAP) were more resistant to TRAIL than U937neo cells and inhibition of XIAP with the small-molecule inhibitor 1396-11 enhanced TRAIL-induced apoptosis, implying XIAP as a resistance factor in AML. Furthermore, triptolide increased DR5 levels in OCI-AML3, while the DR5 increase was blunted in p53-knockdown OCI-AML3 and p53-mutated U937 cells, confirming a role for p53 in the regulation of DR5. In support of this finding, disruption of MDM2-p53 binding with subsequent increase in p53 levels by nutlin3a increased DR5 levels and sensitized OCI-AML3 cells to TRAIL. The combination of 1396-11+nutlin3a+TRAIL was more effective than either the 1396-11+TRAIL or nutlin3a+TRAIL combinations in OCI-AML3 cells further supporting the role of triptolide as a sensitizer to TRAIL-induced apoptosis in part by independent modulation of XIAP expression and p53 signaling. Thus, the combination of triptolide and TRAIL may provide a novel strategy for treating AML by overcoming critical mechanisms of apoptosis resistance.
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