Received on October 23, 2006
Accepted on April 17, 2007

Drug Monitoring and Toxicology

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

¹ Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY, and Department of Life Science, Division of Biomedical and Molecular Sciences, Texas A&M University, Corpus Christi, TX
² Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY
³ Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY, and Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY

^* To whom correspondence should be addressed. 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.