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

Bing Z. Carter, Steven M. Kornblau, Twee Tsao, Rui Yu Wang, Wendy D. Schober, Michele Milella, Hsi Guang Sung, John C. Reed, Michael Andreeff

Research output: Contribution to journalArticle

130 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4179-4186
Number of pages8
JournalBlood
Volume102
Issue number12
DOIs
Publication statusPublished - Dec 1 2003

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Caspase Inhibitors
Cell death
Caspases
Acute Myeloid Leukemia
Cell Survival
Cell Death
Cells
Chemotherapy
Apoptosis
Drug Therapy
Chemical activation
X-Linked Inhibitor of Apoptosis Protein
Apoptosis Inducing Factor
Poly Adenosine Diphosphate Ribose
In Vitro Techniques
Inhibition (Psychology)
Mitochondrial Membrane Potential
Cytarabine
Vincristine
DNA Fragmentation

ASJC Scopus subject areas

  • Hematology

Cite this

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. / Carter, Bing Z.; Kornblau, Steven M.; Tsao, Twee; Wang, Rui Yu; Schober, Wendy D.; Milella, Michele; Sung, Hsi Guang; Reed, John C.; Andreeff, Michael.

In: Blood, Vol. 102, No. 12, 01.12.2003, p. 4179-4186.

Research output: Contribution to journalArticle

Carter, Bing Z. ; Kornblau, Steven M. ; Tsao, Twee ; Wang, Rui Yu ; Schober, Wendy D. ; Milella, Michele ; Sung, Hsi Guang ; Reed, John C. ; Andreeff, Michael. / 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. In: Blood. 2003 ; Vol. 102, No. 12. pp. 4179-4186.
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