title: Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5.
abstract: 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 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.
authors.affiliation: The University of Texas M. D. Anderson Cancer Center, Housto 77030, USA.
authors.forename: Bing Z
authors.initials: BZ
authors.lastname: Carter
authors.forename: Duncan H
authors.initials: DH
authors.lastname: Mak
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Schober
authors.forename: Martin F
authors.initials: MF
authors.lastname: Dietrich
authors.forename: Clemencia
authors.initials: C
authors.lastname: Pinilla
authors.forename: Lyubomir T
authors.initials: LT
authors.lastname: Vassilev
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000814:Aniline Compounds / Q000819:agonists / Q000494:pharmacology / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D004224:Diterpenes / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D004852:Epoxy Compounds / Q000819:agonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000819:agonists / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D010616:Phenanthrenes / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000819:agonists / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020298:U937 Cells; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C520470:1396-11 compound; D000814:Aniline Compounds; D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; D004852:Epoxy Compounds; D007093:Imidazoles; D010616:Phenanthrenes; D010879:Piperazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C001899:triptolide; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2