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Research Articles: Therapeutics, Targets, and Development

Nucleolus and c-Myc: potential targets of cardenolide-mediated antitumor activity

¹ Unibioscreen SA; ² Department of Physiology and Pharmacology, Catholic University of Louvain; ³ Laboratory of Toxicology, Institute of Pharmacy; ⁴ Machine Learning Group, Department of Computer Science, Free University of Brussels; ⁵ MicroArray Unit, Jules Bordet Institute, Brussels, Belgium; and ⁶ University of Rochester, New York, New York

Requests for reprints: Robert Kiss, Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels, Campus de la Plaine CP205/1, Boulevard du Triomphe, 1050 Brussels, Belgium. Phone: 32-477-62-20-83; Fax: 32-2-332-53-35. E-mail: rkiss{at}ulb.ac.be

Abstract

The use of cardenolides like ouabain, digitoxin, or oleandrin has been reported previously many times as a means of potentially combating human refractory prostate cancer by inducing apoptosis through an increase in intracellular calcium concentrations. The aims of the current study were to investigate if part of the antitumor effects mediated by cardenolides concerned disorganization of nucleolar structure and whether this was further associated with a marked decrease in c-Myc expression. Accordingly, the antitumor activity of a novel hemisynthetic cardenolide [1R,3aS,3bR,5aS,6aR,7aS,9R,12aR,13aR,15aR]-3a,11a-dihydroxy-13a-(hydroxymethyl)-9,15a-dimethyl-1-(5-oxo-2,5-dihydrofuran-3-yl)icosahydro-1H,4'H-spiro[cyclopenta [7,8]phenanthro[2,3-b]pyrano[3,2-e][1,4]dioxine-11,2'-[1,3]thiazolidin]-4'-one (UNBS1450)] was compared with that of classic cardenolides and reference anticancer agents in prostate cancer cell lines in vitro and in vivo following s.c. and orthotopic prostate cancer cell grafting into mice. The present study indicates that UNBS1450 markedly decreases the in vitro viability/proliferation of human prostate cancer cell lines but not of normal cells. The induced effects are not linked to an increase in intracellular calcium concentrations and subsequent induction of apoptosis. Rather, they appear to relate to the compound's capacity to disorganize nucleolar structure and function (through an impairment of cyclin-dependent kinase and c-Myc expression and related signaling pathways; paralleled by the disorganization of cancer cell-specific perinucleolar bodies as revealed by disruption of Sam68). This nonapoptotic cancer cell death mediated by severe nucleolar targeting and down-regulation of c-Myc expression is a completely new cardenolide-induced mechanism of antitumor action. [Mol Cancer Ther 2008;7(5):1285–96]

Grant support: Fonds Yvonne Boël (Brussels, Belgium) and Région de Bruxelles-Capitale (Brussels, Belgium). T. Mijatovic and N. De Nève are employees of Unibioscreen SA, Brussels, Belgium. V. Mathieu is the holder of a Grant Télévie from the Fonds National de la Recherche Scientifique (Belgium). C. Decaestecker is a Senior Research Associate and R. Kiss is a Director of Research with the Fonds National de la Recherche Scientifique.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁷ http://www.myc-cancer-gene.org/site/mycTargetDB.asp

⁷ Personal observations.

Received 10/29/07; revised 2/19/08; accepted 3/ 3/08.