title: Pro-death and pro-survival properties of ouabain in U937 lymphoma derived cells.
abstract: BACKGROUND
  Epidemiological studies revealed significantly lower mortality rates in cancer patients receiving cardiac glycosides, which turned on interest in the anticancer properties of these drugs. However, cardiac glycosides have also been shown to stimulate cell growth in several cell types. In the present investigation we analyzed the pro-death and pro-survival properties of ouabain in the human lymphoma derived cell line U937.
  
  
  METHODS
  ROS, intracellular Ca++, cell cycle were evaluated by loading the cells with fluorescent probes under cytofluorimetry. Cell counts and evaluation of trypan blue-excluding cells were performed under optic microscope. Protein detection was done by specific antibodies after protein separation from cellular lysates by SDS-PAGE and transfer blot.
  
  
  RESULTS
  High doses of ouabain cause ROS generation, elevation of [Ca++]i and death of lymphoma derived U937 cells. Lower doses of OUA activate a survival pathway in which plays a role the Na+/Ca++-exchanger (NCX), active in the Ca++ influx mode rather than in the Ca++ efflux mode. Also p38 MAPK plays a pro-survival role. However, the activation of this MAPK does not appear to depend on NCX.
  
  
  CONCLUSIONS
  This investigation shows that the cardiac glycoside OUA is cytotoxic also for the lymphoma derived cell line U937 and that can activate a survival pathway in which are involved NCX and p38 MAPK. These molecules can represent potential targets of combined therapy.
authors.affiliation: Department of Experimental Medicine, University of Rome La Sapienza, Viale Regina Elena 324, Rome 00161, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cuozzo
authors.forename: Marisa
authors.initials: M
authors.lastname: Raciti
authors.forename: Laura
authors.initials: L
authors.lastname: Bertelli
authors.forename: Rosanna
authors.initials: R
authors.lastname: Parente
authors.forename: Livia
authors.initials: L
authors.lastname: Di Renzo
mesh_terms: D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D010042:Ouabain / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D019831:Sodium-Calcium Exchanger; D010042:Ouabain; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium