Digitoxin, in non-toxic concentrations, inhibits proliferation and induces cell death in prostate cancer cell lines

 

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Zusammenfassung

In einer früheren Studie fanden wir eine Apoptosis-Induktion in menschlichen Leukämie-Zelllinien durch Digitoxin. Die wichtigste bekannte pharmakologische Wirkung von Digitoxin ist eine Na+/K+ATPase-Hemmung. Es wurde in der Tat die Meinung geäußert, dass Na+/K+ATPase der tatsächliche Androgen-Rezeptor der Prostata sei. Daher ist es von Interesse, die Wirkungen der klinisch -eingesetzten Herzglykoside Digoxin und Digitoxin auf die menschlichen Prostatakrebs-Zelllinien zu untersuchen. In der aktuellen Studie beurteilten wir die Prostatakrebs-Zelllinien LNCaP, PC-3, TSU-pr1 sowie DU-145 auf ihre Empfindlichkeit gegenüber Digoxin und Digitoxin. Digo-xin induzierte in klinisch relevanten Konzentrationen eine geringe Hemmung der Lebensfähigkeit, während Digitoxin alle 4 Zelllinien stark hemmte. Eine Analyse des DNA-Histogramms zeigte eine Anhäufung der mit Digitoxin behandelten Zellen in der G₂M-Phase des Zellzyklus sowie eine DNA-Fragmentierung. Daten über die Proliferation, MTT-Daten sowie DNA-Histogramme zeigten zusammen mit der Phasenkontrastmikroskopie ein durch Apoptosis induziertes Absterben der Zellen. Diese Ergebnisse implizieren eine mögliche Rolle der Herzglykoside bei der Behandlung von Prostatakrebs.

Summary

In an earlier study we found apoptosis induction in human leukemia cell lines by digitoxin. The main known pharmacological effect of digitoxin is Na+/K+ATPase inhibition. In fact, the Na+/K+ATPase has been proposed to be the actual androgen receptor of the prostate. Hence, it is of interest to examine the effects of the clinically used cardiac glycosides digoxin and digitoxin on human prostate cancer cell lines. In the present study we assessed the cancer prostate cell lines LNCaP, PC-3, TSU-pr1 and DU-145 for susceptibility to digoxin and digitoxin. Digoxin, in clinically relevant concentrations, induced minor inhibition of viability, whereas digitoxin potently inhibited all 4 cell lines. DNA histogram analysis revealed an accumulation of the digitoxin treated cells in the G₂M phase of the cell cycle as well as DNA fragmentation. Proliferation data, MTT data and DNA histograms together with phase contrast light microscopy indicated cell death induced through apoptosis. These results imply a possible role for cardiac glycosides in the management of prostate cancer.

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Correspondence to:

Dr. Johan Haux

Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology

N-7489 Trondheim, Norway

Phone: +int 73598669 or 8660

Fax: +int 47 73598801

Email: Johan.Haux@medisin.ntnu.no