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

• 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
• ISSN: 0008-5472; 1538-7445

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.