Abstract
BackgroundDespite years of interest in the anti-cancerous effects of cardiac glycosides (CGs), and numerous studies in vitro and in animals, it has not yet been possible to utilize this potential clinically. Reports have demonstrated promising in vitro effects on different targets as well as a possible therapeutic index/selectivity in vitro and in experimental animals. Recently, however, general inhibition of protein synthesis was suggested as the main mechanism of the anti-cancerous effects of CGs. In addition, evidence of species differences of a magnitude sufficient to explain the results of many studies called for reconsideration of earlier results.Principal FindingsIn this report we identified primary B-precursor and T-ALL cells as being particularly susceptible to the cytotoxic effects of CGs. Digitoxin appeared most potent and IC50 values for several patient samples were at concentrations that may be achieved in the clinic. Significant protein synthesis inhibition at concentrations corresponding to IC50 was demonstrated in colorectal tumour cell lines moderately resistant to the cytotoxic effects of digoxin and digitoxin, but not in highly sensitive leukaemia cell lines.ConclusionIt is suggested that further investigation regarding CGs may be focused on diagnoses like T- and B-precursor ALL.
Highlights
Cardiac glycosides (CGs) are a group of plant-derived compounds that have been used for many years in traditional medicine and that are currently used in treatment of cardiac failure and atrial fibrillation
The cytotoxic activities of digitoxin and ouabain were studied in primary leukaemic cells: T-acute lymphoblastic leukaemia (ALL) (n = digitoxin 4; ouabain 7), Bprecursor ALL (n = 10; 6), acute myeloid leukaemia (AML) (n = 11;11), chronic lymphocytic leukaemia (CLL) (n = 9; 6) and peripheral blood mononuclear cells (PBMCs) (n = 4; 8) using the fluorometric microculture cytotoxicity assay (FMCA)
Similar tests on the activity of digoxin, digitoxin and ouabain were performed in the leukaemia cell lines CCRF-CEM and SUP-B15
Summary
Cardiac glycosides (CGs) are a group of plant-derived compounds that have been used for many years in traditional medicine and that are currently used in treatment of cardiac failure and atrial fibrillation In parallel to this use, CGs have received attention as potential drugs in the treatment of various malignant diseases. Calcium-dependent activation of caspases and other hydrolytic enzymes [7,12,13], generation of reactive oxygen species (ROS) [14], topoisomerase inhibition [15], interference with signal transduction pathways (e.g. Src-mediated phosphorylation of epidermal growth factor receptor (EGFR) and induction of the cell cycle inhibitor p21Cip1 [16] have all been associated with the anti-tumour effects of CGs. Despite years of interest in the anti-cancerous effects of cardiac glycosides (CGs), and numerous studies in vitro and in animals, it has not yet been possible to utilize this potential clinically. Evidence of species differences of a magnitude sufficient to explain the results of many studies called for reconsideration of earlier results
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