Abstract
BackgroundEpidemiological 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.MethodsROS, 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.ResultsHigh 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.ConclusionThis 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.
Highlights
Epidemiological studies revealed significantly lower mortality rates in cancer patients receiving cardiac glycosides, which turned on interest in the anticancer properties of these drugs
SubG1 events were studied by cytofluorimetry of cell cycle phases of cells fixed and stained with propidium iodide: hypodiploid DNA events are discernable from the narrow peak of cells with diploid DNA content, and are considered to be indicative of apoptotic nuclei [23,24]
Cell counts indicated that at this concentration OUA did not allow cell growth. These results suggest that OUA ≥500 nM causes U937 cell death, while OUA 100 nM does not allow cell growth and causes activation of a survival pathway in most U937 cells, increasing the time spent in the G1 cell cycle phase
Summary
Epidemiological studies revealed significantly lower mortality rates in cancer patients receiving cardiac glycosides, which turned on interest in the anticancer properties of these drugs. The Na+/K+ ATPase catalyzes the electrogenic exchange of three intracellular Na+ ions for two extracellular K+ ions using for this transport energy that is released from the hydrolysis of ATP In this way Na+/K+ ATPase plays an important role in the regulation of intracellular Na+ and K+ concentrations and in the maintenance of electrical membrane potential, cell volume, and Na+-coupled transport of amino acids, glucose, nucleotides, and other compounds with low molecular mass [1,2,3]. NCX is one of the main pathways for intracellular Ca++ clearance [9] and the inhibition of the Na+/K+ ATPase by cardiac glycosides, causing the inversion of the Na+/K+ gradient, leads to impairment of the NCX activity, contributing to accumulation of Ca++ [4,5,6,7,8,9]
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