Nucleolus and c-Myc: potential targets of cardenolide-mediated antitumor activity.
Mijatovic T, De Neve N, Gailly P, Mathieu V, Haibe-Kains B, Bontempi G, Lapeira J, Decaestecker C, Facchini V and Kiss R
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 anti tumor 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-dihy-
drofuran-3-yl)icosahydro-1H,4H -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.