Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells

Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells

Cardiac glycosides are used clinically to increase contractile force in patients with cardiac disorders. Their mechanism of action is well established and involves inhibition of the plasma membrane Na+/K+-ATPase, leading to alterations in intracellular K+ and Ca(2+) levels. Here, we report that the...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Vol. 60; no. 14; pp. 3807 - 3812
Main Authors: MCCONKEY, D. J, YUN LIN, NUTT, L. K, OZEL, H. Z, NEWMAN, R. A
Format: Journal Article
Language:English
Published: Philadelphia, PA American Association for Cancer Research 15-07-2000
Subjects:
Adenocarcinoma - metabolism
Adenocarcinoma - pathology
Antineoplastic agents
Apoptosis - drug effects
Biological and medical sciences
Calcium - metabolism
Cardenolides - pharmacology
Cardiac Glycosides - pharmacology
Cardiotonic Agents - pharmacology
Caspase 3
Caspase 8
Caspase 9
Caspases - metabolism
Cell Separation
Chemotherapy
Cytochrome c Group - metabolism
Digoxin - pharmacology
DNA Fragmentation - drug effects
Dose-Response Relationship, Drug
Flow Cytometry
Humans
Male
Medical sciences
Myocardium - metabolism
Ouabain - pharmacology
Pharmacology. Drug treatments
Poly(ADP-ribose) Polymerases - metabolism
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Time Factors
Tumor Cells, Cultured
Adenocarcinoma
Antineoplastic agent
Heart
Prostate disease
Digoxin
Tumoral tissue
Ouabain
Signal transduction
Calcium ion
Established cell line
Glycoside
Male genital diseases
Tumor cell
Digitalis drug
Human
Urinary system disease
Androgen
Malignant tumor
In vitro
Biological activity
Cell death
Metastatic
Intracellular
Prostate
Apoptosis
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Summary:Cardiac glycosides are used clinically to increase contractile force in patients with cardiac disorders. Their mechanism of action is well established and involves inhibition of the plasma membrane Na+/K+-ATPase, leading to alterations in intracellular K+ and Ca(2+) levels. Here, we report that the cardiac glycosides oleandrin, ouabain, and digoxin induce apoptosis in androgen-independent human prostate cancer cell lines in vitro. Cell death was associated with early release of cytochrome c from mitochondria, followed by proteolytic processing of caspases 8 and 3. Oleandrin also promoted caspase activation, detected by cleavage poly(ADP-ribose) polymerase and hydrolysis of a peptide substrate (DEVD-pNA). Comparison of the rates of apoptosis in poorly metastatic PC3 M-Pro4 and highly metastatic PC3 M-LN4 subclones demonstrated that cell death was delayed in the latter because of a delay in mitochondrial cytochrome c release. Single-cell imaging of intracellular Ca(2+) fluxes demonstrated that the proapoptotic effects of the cardiac glycosides were linked to their abilities to induce sustained Ca(2+) increases in the cells. Our results define a novel activity for cardiac glycosides that could prove relevant to the treatment of metastatic prostate cancer.
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ISSN:0008-5472
1538-7445