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

David J. McConkey, Yun Lin, Leta K. Nutt, Huseyin Z. Ozel, Robert A. Newman

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3807-3812
Number of pages6
JournalCancer Research
Volume60
Issue number14
StatePublished - Jul 15 2000

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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