title: Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients.
abstract: The cardiac glycosides digitoxin (1) and digoxin (3) have been used in cardiac diseases for many years. During this time several reports have suggested the possible use of digitalis in medical oncology. Several analogues of digitoxin (1) were evaluated for growth inhibition activity in three human cancer cell lines; this study showed that digitoxin (1) was the most active compound and revealed some structural features that may play a role in the growth inhibition activity of these drugs. The IC50 values for 1 (3-33 nM) were within or below the concentration range seen in the plasma of patients with cardiac disease receiving this glycoside (20-33 nM). A renal adenocarcinoma cancer cell line (TK-10) was hypersensitive to this drug, and digitoxin toxicity on these cells was mediated by apoptosis. In vitro experiments showed that 1 at 30 nM induced levels of DNA-topoisomerase II cleavable complexes similar to etoposide, a topoisomerase II poison widely used in cancer chemotherapy. Using the individual cell assay TARDIS, cells exposed to 1 for 30 min showed low but statistically significant levels of DNA-topoisomerase II cleavable complexes; however these complexes disappeared after 24 h exposure.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41011, Seville, Spain. mlopezlazaro@us.es
authors.forename: Miguel
authors.initials: M
authors.lastname: López-Lázaro
authors.forename: Nuria
authors.initials: N
authors.lastname: Pastor
authors.forename: Sami S
authors.initials: SS
authors.lastname: Azrak
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Ayuso
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Austin
authors.forename: Felipe
authors.initials: F
authors.lastname: Cortés
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004074:Digitoxin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D004074:Digitoxin; D004250:DNA Topoisomerases, Type II