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Clinical Chemistry 53: 1315-1322, 2007. First published May 10, 2007; 10.1373/clinchem.2006.082081
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(Clinical Chemistry. 2007;53:1315-1322.)
© 2007 American Association for Clinical Chemistry, Inc.

Drug Monitoring and Toxicology

Digoxin-Like Immunoreactive Factors Induce Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia

Kenneth Ihenetu1,3, Hassan M. Qazzaz1, Fabian Crespo1, Rafael Fernandez-Botran1 and Roland Valdes, Jr1,2,a

Departments of1 Pathology and Laboratory Medicine and 2 Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY.

aAddress correspondence to this author at: Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, MDR Bldg., Rm. 209, 511 South Floyd St., Louisville, KY 40202. Fax 502-852-1771; e-mail: rvaldes{at}louisville.edu

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 (IC50), 24 nmol/L; ouabain IC50, 26 nmol/L]. Neither digoxin nor ouabain induced apoptosis in K-562 cells or PBMCs. DLIF was more potent (IC50, 1.9 nmol/L) and >2-fold more effective than digoxin or ouabain at inducing maximum apoptosis in Jurkat cells. The IC50 values in the apoptosis assays were >100-fold lower (DLIF) and 20-fold lower (digoxin and ouabain) than the IC50 required for Na+- and K+-dependent ATPase (DLIF, 200 nmol/L; digoxin, 910 nmol/L; ouabain, 600 nmol/L).

Conclusion: 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.






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