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.