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Cardiac Glycosides Stimulate Ca²⁺ Increases and Apoptosis in Androgen-independent, Metastatic Human Prostate Adenocarcinoma Cells

Departments of Cancer Biology [D. J. M., L. K. N.] and Experimental Therapeutics [Y. L., R. A. N.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Ozelle Pharmaceuticals, Inc., San Antonio, Texas 78230 [H. Z. O.]

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 Ca²⁺ 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 Ca²⁺ fluxes demonstrated that the proapoptotic effects of the cardiac glycosides were linked to their abilities to induce sustained Ca²⁺ 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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