Digoxin-like immunoreactive factors induce apoptosis in human acute T-cell lymphoblastic leukemia.
BACKGROUND
Plant-derived cardenolides reportedly possess anticancer properties in human leukemic cells via selective induction of apoptosis, cell cycle arrest, and differentiation. Selective induction of apoptosis with mammalian-derived digoxin-like immunoreactive factor (DLIF) could provide new strategies for anticancer drug development or the identification of biomarkers for cancer. We investigated whether DLIFs selectively induce apoptosis in human lymphoblastic leukemic cells.


METHODS
We compared the relative potencies of digoxin, ouabain, and DLIF on induction of programmed cell death in Jurkat cells (an acute T-leukemic cell line), K-562 (a myelogenous leukemia cell line), and nonpathologic human peripheral blood mononuclear cells (PBMCs). Apoptosis was measured by flow cytometry with the annexin V/propidium iodide method.


RESULTS
Digoxin and ouabain induced apoptosis in Jurkat cells [digoxin 50% inhibitory concentration (IC(50)), 24 nmol/L; ouabain IC(50), 26 nmol/L]. Neither digoxin nor ouabain induced apoptosis in K-562 cells or PBMCs. DLIF was more potent (IC(50), 1.9 nmol/L) and >2-fold more effective than digoxin or ouabain at inducing maximum apoptosis in Jurkat cells. The IC(50) values in the apoptosis assays were >100-fold lower (DLIF) and 20-fold lower (digoxin and ouabain) than the IC(50) required for Na(+)- and K(+)-dependent ATPase (DLIF, 200 nmol/L; digoxin, 910 nmol/L; ouabain, 600 nmol/L).


CONCLUSIONS
DLIF selectively induces apoptosis in a human acute T-cell lymphoblastic leukemia cell line but not in K-562 cells or PBMCs. These data suggest a new physiological role for these endogenous hormone-like factors.
Ihenetu
Kenneth
K
Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Qazzaz
Hassan M
HM
Crespo
Fabian
F
Fernandez-Botran
Rafael
R
Valdes
Roland
R
D000293:Adolescent; D017209:Apoptosis; D002298:Cardenolides / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D004077:Digoxin / Q000494:pharmacology*; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008297:Male; D010042:Ouabain / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012503:Saponins / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D002298:Cardenolides; D053222:Fas Ligand Protein; D012333:RNA, Messenger; D012503:Saponins; C034504:digoxin-like factors; D010042:Ouabain; D004077:Digoxin; D053148:Caspase 3; D000254:Sodium-Potassium-Exchanging ATPase