Human monocytoid leukemia cells are highly sensitive to apoptosis induced by 2'-deoxycoformycin and 2'-deoxyadenosine: association with dATP-dependent activation of caspase-3.
The adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (dCF) significantly inhibits the proliferation of leukemia and lymphoma cell lines. When cells were incubated in the presence of both dCF and 2'-deoxyadenosine (dAd), the concentration of dCF required to induce apoptosis of monocytoid leukemia cells was much lower than that required for myeloid, erythroid, or lymphoma cell lines. Among the cell lines tested, U937 cells were the most sensitive to this treatment. The concentration of dCF that effectively inhibited the proliferation of U937 cells was 1/1,000 of that required for lymphoma cell lines, on a molar basis. However, the uptake of dCF or dAd in U937 cells was comparable with that in other leukemia and lymphoma cell lines. The intracellular accumulation of dATP in U937 cells was only slightly higher than that in other leukemia cells in dCF-treated culture. Treatment with dCF plus dAd induced apoptosis in U937 cells at low concentrations, and this apoptosis was reduced by treatment with caspase inhibitors. Induction of caspase-3 (CPP32) activity accompanied the apoptosis induced by dCF plus dAd. No activation of CPP32 was observed in cytosol prepared from exponentially growing leukemia and lymphoma cells. However, dATP effectively induced CPP32 activation in cytosol from monocytoid cells, but not in that from nonmonocytoid cells, suggesting that dATP-dependent CPP32 activation is at least partly involved in the preferential induction of apoptosis in monocytoid leukemia cells. The combination of dCF and dAd may be useful for the clinical treatment of acute monocytic leukemia.
Niitsu
N
N
Department of Chemotherapy, Saitama Cancer Center Research Institute, Saitama, University School of Medicine, Tokyo, Japan.
Yamaguchi
Y
Y
Umeda
M
M
Honma
Y
Y
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000473:pathology; D007948:Leukemia, Monocytic, Acute / Q000201:enzymology / Q000473:pathology*; D008223:Lymphoma / Q000201:enzymology / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D015649:Pentostatin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020298:U937 Cells / Q000187:drug effects* / Q000201:enzymology
D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D006131:Growth Inhibitors; D009363:Neoplasm Proteins; D015649:Pentostatin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C026600:2'-deoxyadenosine triphosphate; C058118:2'-deoxyadenosine