Investigation of ouabain-induced anticancer effect in human androgen-independent prostate cancer PC-3 cells
Journal
Biochemical Pharmacology
Journal Volume
67
Journal Issue
4
Pages
727-733
Date Issued
2004
Author(s)
Abstract
To determine the therapeutic potential of cardiac glycosides in androgen-independent prostate cancer, we examined ouabain-induced cytotoxic effect as well as the signaling pathways in PC-3 cells. Ouabain induced a time- and concentration-dependent cytotoxicity using mitochondrial MTT reduction assays, and the effective threshold concentration was in nanomolar level. At the concentrations less than 10nM, ouabain induced a decrease of mitochondrial activity until a 7-hr exposure was performed, while it induced a rapid drop of mitochondrial function as early as a 2-hr treatment of cells with high concentrations of ouabain suggesting the involvement of two distinct mechanisms to ouabain action. After functional examinations, the data showed that both low and high concentrations of ouabain induced an inhibition of Na +-K+ ATPase and a subsequent 45Ca2+ influx into PC-3 cells. High concentrations of ouabain induced a significant and time-dependent loss of mitochondrial membrane potential (Δψ m), a sustained production of reactive oxygen species (ROS), and severe apoptotic reaction. Ouabain also induced an increase of Par-4 (prostate apoptosis response 4) expression. Furthermore, an antisense, but not nonsense, oligomer against Par-4 expression significantly inhibited the cytotoxicity induced by low concentrations of ouabain. It is suggested that ouabain induces two modes of cytotoxic effect in human hormone-independent prostate cancer PC-3 cells. Low concentrations of ouabain induce the increase of Par-4 expression and sensitize the cytotoxicity; while high concentrations of ouabain induce a loss of Δψm, a sustained ROS production and a severe apoptosis in PC-3 cells. ? 2003 Elsevier Inc. All rights reserved.
SDGs
Other Subjects
3 (4,5 dimethyl 2 thiazolyl) 2,5 diphenyltetrazolium bromide; adenosine triphosphatase (potassium sodium); androgen; calcium ion; cardiac glycoside; hormone; ouabain; prostate apoptosis response 4; protein; reactive oxygen metabolite; unclassified drug; antineoplastic activity; apoptosis; article; calcium transport; cancer cell; concentration response; controlled study; cytotoxicity; drug determination; drug effect; drug exposure; drug mechanism; enzyme inhibition; human; human cell; inhibition kinetics; maximum allowable concentration; membrane potential; mitochondrial membrane; mitochondrion; priority journal; prostate cancer; protein expression; signal transduction; time
Publisher
Elsevier Inc.
Type
journal article