Research Article: Cardiac Glycosides Induce Cell Death in Human Cells by Inhibiting General Protein Synthesis

Date Published: December 16, 2009

Publisher: Public Library of Science

Author(s): Andrea Perne, Markus K. Muellner, Magdalena Steinrueck, Nils Craig-Mueller, Julia Mayerhofer, Ilse Schwarzinger, Mathew Sloane, Iris Z. Uras, Gregor Hoermann, Sebastian M. B. Nijman, Matthias Mayerhofer, Alfred Lewin.

Abstract: Cardiac glycosides are Na+/K+-pump inhibitors widely used to treat heart failure. They are also highly cytotoxic, and studies have suggested specific anti-tumor activity leading to current clinical trials in cancer patients. However, a definitive demonstration of this putative anti-cancer activity and the underlying molecular mechanism has remained elusive.

Partial Text: The positive inotropic effects of Digitalis purpurea extracts were first recognized over two centuries ago and digitalis-like compounds (also called cardiac glycosides (CGs) or cardiotonic steroids) are still widely used in the treatment of chronic heart failure [1]. Since the mid 1960s numerous papers have proposed putative anti-cancer effects of CGs [1], [2], [3], [4]. CGs show in vitro activity against a broad range of cell types and a number of compound screens have recently rediscovered that CGs inhibit proliferation in various assays [2], [5], [6], [7]. A putative anti-cancer activity for CGs is supported by several case-control and cohort studies that loosely correlated CG treatment with lower cancer recurrence or incidence [8], [9], [10], [11], [12]. Furthermore, using mouse models, CGs were shown to inhibit skin carcinogenesis and reduce xenograft tumor load [6], [13], [14], [15], [16]. Particularly the strong effects in xenograft mouse models have provided a basis for the current clinical testing of these drugs and their derivatives ( id. NCT00281021, NCT00650910 NCT00017446,

Our findings challenge the view that CGs or other Na+/K+-ATPase inhibitors hold promise as anti-cancer drugs and therefore have immediate consequences for the clinical evaluation of CGs as anti-neoplastic agents. There are at least four ongoing clinical trials in the United States and Europe testing the effect of CGs and a CG-derivative in cancer ( id. NCT00281021, NCT00650910 NCT00017446,



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