title: 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.
abstract: Survivin and XIAP, members of the protein family known as the inhibitors of apoptosis, interfere with the activation of caspases, called the "cell death executioners." We examined Survivin (n = 116) and XIAP (n = 172) expression in primary acute myeloid leukemia (AML) blasts and assessed the impact of their expression on prognosis. They were detected in all samples analyzed. However, no correlation was observed with cytogenetics, remission attainment, or overall survival of patients with AML. To investigate the importance of caspases in chemotherapy-induced apoptosis in AML, we treated OCI-AML3 cells with Ara-C, doxorubicin, vincristine, and paclitaxel, which induced caspase cleavage and apoptosis. Blocking of caspase activation by pan-caspase inhibitor abolished poly(adenosine diphosphate [ADP]-ribose) polymerase cleavage and DNA fragmentation but did not prevent chemotherapy-induced cell death and did not inhibit, or only partially inhibited, mitochondrial release of cytochrome c, Smac, apoptosis-inducing factor (AIF), or loss of mitochondrial membrane potential. Caspase inhibition also did not protect AML blasts from chemotherapy-induced cell death in vitro. These results suggest that expression levels of Survivin or XIAP have no prognostic impact in AML patients. Although anticancer drugs induced caspase cleavage and apoptosis, cell killing was caspase independent. This may partially explain the lack of prognostic impact of XIAP and Survivin and may suggest caspase-independent mechanisms of cell death in AML.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 448, Houston, TX 77030, USA.
authors.forename: Bing Z
authors.initials: BZ
authors.lastname: Carter
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: Twee
authors.initials: T
authors.lastname: Tsao
authors.forename: Rui-Yu
authors.initials: RY
authors.lastname: Wang
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Schober
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.forename: Hsi-Guang
authors.initials: HG
authors.lastname: Sung
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000473:pathology; D061945:Caspase Inhibitors; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007951:Leukemia, Myeloid / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000032:analysis* / Q000502:physiology; D009363:Neoplasm Proteins; D011379:Prognosis; D011506:Proteins / Q000032:analysis* / Q000502:physiology; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human