The nucleolus, a potential target of cardenolide-mediated anti-tumor activity
Mijatovic T, De Nève N, Gailly P, Mathieu V, Haibe-Kains B, Bontempi G, Decaestecker C, Facchini V, 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 intra-cellular calcium
concentrations (a mechanism also commonly associated with the adverse
effects of cardenolides). The structural variety of cardiotonic
steroids seems to offer a multiplicity of compounds with undiscovered
mechanisms of action. The present study indicates that the structurally
novel new 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 (coded UNBS1450), markedly decreases the
in vitro viability/proliferation of human prostate cancer cell lines
and in vivo the development of both subcutaneous and orthotopic
xenografts of the PC-3 model in immunocompromized mice. ROS induction
by several cardenolides is well documented and correlates with a
loss in cell viability, proliferation and defense mechanisms. A marked
time and concentration dependent ROS increase was demonstrated
following UNBS1450 treatment (10 and 100nM). However, the induced
effects are not linked to an increase in intra-cellular calcium
concentrations and subsequent induction of apoptosis, as observed with
classic cardenolides. Rather, the induced effects appear to relate to
the compound’s capacity to disorganize nucleolar structure and function
through an impairment of CDK and c-Myc expression and related signaling
pathways. The marked UNBS1450-induced c-Myc down-regulation could
result, at least partly, from rapid compound-induced increases in ROS.
The nucleolar disorganization at concentrations which markedly impair
prostate cancer cell proliferation (paralleled by the disorganization
of cancer cell-specific perinucleolar bodies as revealed by disruption
of Sam68) is not observed in normal cells. This non-apoptotic cancer
cell death mediated by severe nucleolar targeting is a completely new
cardenolide-induced mechanism of anti-tumor action.