Assessment of the downstream portion of the mitochondrial pathway of caspase activation in patients with acute myeloid leukemia.
Most chemotherapeutic agents used in the treatment of acute myeloid leukemia (AML) induce apoptosis by triggering the mitochondrial pathway of caspase activation. To investigate the downstream portion of the mitochondrial pathway of caspase activation in patients with AML, cytosolic lysates were stimulated with cytochrome c and dATP and hydrolysis of Ac-DEVD-AFC by effector caspases was measured. Defects in the distal mitochondrial pathway were more common in samples from patients with AML that relapsed rapidly after induction chemotherapy compared to samples from treatment naïve patients. The incidence of blocked pathways did not differ based on response to induction chemotherapy, as even nonresponders generally had an intact pathway. When the distal mitochondrial pathway was blocked, defects were usually at the level of the effector caspases. Thus, functional defects in the distal portion of the mitochondrial pathway of caspase activation may help explain the nature of response and relapse after treatment.
Gronda
M
M
The Princess Margaret Hospital and the Ontario Cancer Institute, Toronto, ON, Canada.
Brandwein
J
J
Minden
M D
MD
Pond
G R
GR
Schuh
A C
AC
Wells
R A
RA
Messner
H
H
Chun
K
K
Schimmer
A D
AD
D000255:Adenosine Triphosphate / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology*; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008954:Models, Biological
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D053148:Caspase 3; D020169:Caspases