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

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.
AuthorsTatjana Mijatovic, Nancy De Nève, Philippe Gailly, Véronique Mathieu, Benjamin Haibe-Kains, Gianluca Bontempi, Javier Lapeira, Christine Decaestecker, Vincenzo Facchini, Robert Kiss
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 5 Pg. 1285-96 (May 2008) ISSN: 1535-7163 [Print] United States
PMID18483316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Cardenolides
  • Proto-Oncogene Proteins c-myc
  • UNBS 1450
  • Calcium
Topics
  • Animals
  • Antineoplastic Agents (therapeutic use)
  • Apoptosis
  • Calcium (metabolism)
  • Cardenolides (therapeutic use)
  • Cell Nucleolus (drug effects, ultrastructure)
  • Cell Proliferation
  • Down-Regulation
  • Humans
  • Male
  • Mice
  • Prostatic Neoplasms (drug therapy, metabolism, ultrastructure)
  • Proto-Oncogene Proteins c-myc (genetics, metabolism)
  • Tumor Cells, Cultured

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