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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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NEOPLASIA

Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5

Bing Z. Carter1, Duncan H. Mak1, Wendy D. Schober1, Martin F. Dietrich1, Clemencia Pinilla2, Lyubomir T. Vassilev3, John C. Reed4, and Michael Andreeff1

1 The University of Texas M. D. Anderson Cancer Center, Houston; 2 Torrey Pines Institute for Molecular Studies, La Jolla, CA; 3 Roche Pharmaceuticals, Nutley, NJ; and 4 Burnham Institute for Medical Research, La Jolla, CA

Acute myeloid leukemia (AML) cells are relatively resistant to tumor necrosis factor {alpha}–related apoptosis-inducing ligand (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 plus nutlin3a plus TRAIL was more effective than either the 1396-11 and TRAIL or nutlin3a and TRAIL combinations in OCI-AML3 cells, further supporting the role of triptolide as a sensitizer to TRAILinduced 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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