ABSTRACT
We investigated the involvement of intracellular cAMP in endothelial cell injury induced by epirubicin. Epirubicin-induced decrease in cell viability and increase in caspase-3/7 activity were reversed by a cAMP analog dibutyryl cAMP (DBcAMP) or an activator of adenylate cyclase forskolin concomitant with a phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Moreover, epirubicin-induced elevation of lipid peroxide levels was attenuated by DBcAMP. Interestingly, the exposure of epirubicin decreased intracellular cAMP levels before the onset of epirubicin-induced production of lipid peroxidation. These results suggest that intracellular cAMP plays an important role in epirubicin-induced endothelial cell injury.
Subject(s)
Apoptosis/drug effects , Cyclic AMP/physiology , Endothelial Cells/drug effects , Endothelial Cells/pathology , Epirubicin/adverse effects , Epirubicin/antagonists & inhibitors , 1-Methyl-3-isobutylxanthine/pharmacology , Albuterol, Ipratropium Drug Combination , Animals , Bucladesine/pharmacology , Caspase 3/metabolism , Caspase 7/metabolism , Cell Survival/drug effects , Cells, Cultured , Colforsin/pharmacology , Cyclic AMP/metabolism , Endothelial Cells/metabolism , Lipid Peroxidation/drug effects , Lipid Peroxides/metabolism , SwineABSTRACT
The anti-tumor effects of selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) on several types of cancer cells have been reported. However, comparison of the anti-tumor effects of these drugs on human hepatocellular carcinoma (HepG2) cells has not been studied. We compared the anti-tumor effects of four SSRIs and two SNRIs on HepG2 cells. SSRIs and duloxetine dose-dependently decreased cell viability. Milnacipran had no effect on cell viability. The half-maximal inhibitory concentration was lower in the order of: sertraline, paroxetine, duloxetine, fluvoxamine, escitalopram, and milnacipran. Exposure to sertraline (2 µM) significantly increased caspase-3/7 activity. These results suggest that, of the agents tested here, sertraline had the highest sensitivity to HepG2 cells, and activation of the caspase pathway is involved in the anti-tumor effects of sertraline in HepG2 cells.
