Enhanced ability of daniplestim and myelopoietin-1 to suppress apoptosis in human hematopoietic cells.
Modified and chimeric cytokines have been developed to aid in the recovery of hematopoietic precursor cells after myeloablative chemotherapy. The interleukin-3 (IL-3) receptor agonist, daniplestim, binds to the IL-3 receptor-alpha subunit with 60-fold greater affinity and induces cell proliferation and colony-forming unit formation 10- to 22-fold better than native IL-3. A chimeric cytokine, myelopoietin-1, composed of daniplestim and a G-CSF receptor agonist binds both the IL-3 and G-CSF receptors. While the in vivo effects of daniplestim and myelopoietin-1 are well described, the mechanisms by which they stimulate growth are not well understood. We have investigated the effects of daniplestim and myelopoietin-1 on the prevention of apoptosis in two human hematopoietic cell lines, OCI-AML.5 and AML 193. Daniplestim and myelopoietin-1 prevented apoptosis to a greater degree than native recombinant IL-3 or G-CSF as determined by annexin V/propidium iodide binding and TUNEL assays. Daniplestim and myelopoietin-1 promoted the maintenance of the mitochondrial membrane potential better than native IL-3 or G-CSF. These cytokines promoted a lower redox potential as higher levels of free radicals were detected after cytokine treatment than in cytokine-deprived cells implying increased respiration. These results indicate that daniplestim and myelopoietin-1 are able to prevent apoptosis in hematopoietic cells more effectively than native IL-3 and G-CSF. These effects of daniplestim and myelopoietin-1 may contribute to their effective ability to repopulate hematopoietic precursor cells after chemotherapy.
McCubrey
J A
JA
Department of Microbiology and Immunology, Leo Jenkins Cancer Center, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
Blalock
W L
WL
Saleh
O
O
Pearce
M
M
Burrows
C
C
Steelman
L S
LS
Lee
J T
JT
Franklin
R A
RA
Oberhaus
S M
SM
Moye
P W
PW
Doshi
P D
PD
McKearn
J P
JP
D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation; D019070:Cell Lineage; D016179:Granulocyte Colony-Stimulating Factor; D006410:Hematopoiesis; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D007377:Interleukin-3 / Q000031:analogs & derivatives; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins
D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor; C093340:daniplestim