IkBa
We
investigated whether inhibition of NFkB increases the efficacy of cisplatin in
in vitro and in vivo ovarian cancer models. We compared the basal levels of
phosphorylation of IkBa and activity of NFkB between cisplatin-sensitive A2780
cells and cisplatin-resistant Caov-3 cells. The basal levels of phosphorylation
of IkBa and activity of NFkB in Caov-3 cells were significantly higher than
those in A2780 cells. Cisplatin caused a more marked decrease in the
phosphorylation of IkBa and activity of NFkB in A2780 cells than in Caov-3 cells.
Thus, high basal levels of phosphorylation of IkBa and activation of NFkB, and
less marked inhibition of the phosphorylation of IkBa and activation of NFkB by
cisplatin, seem to reduce the sensitivity of cells to cisplatin. Inhibition of
NFkB activity either by treatment with IkBa phosphorylation inhibitor (BAY
11-7085) or a specific NFkB nuclear translocation inhibitor (SN-50) or by
transfection of p50DNLS (which lacks the nuclear localization signal domain)
increased the efficacy of both the cisplatin-induced attenuation of IkBa
phosphorylation and NFkB activity and the cisplatin-induced apoptosis. In
addition, treatment with BAY 11-7085 increased the efficacy of the
cisplatin-induced attenuation of both the expression of XIAP and the cell
invasion through Matrigel. Moreover, treatment with BAY 11-7085 increased the
efficacy of the cisplatin-induced inhibition of the intraabdominal
dissemination and production of ascites using athymic nude mice inoculated i.p.
with Caov-3 cells. These results suggest that combination therapy of cisplatin
with NFkB inhibitor would increase the therapeutic efficacy of cisplatin.
PMID: 15026414 [PubMed - as supplied by publisher
NFkappaB is
an important and ubiquitous transcription factor formed by various homo- and
heterodimers of the NFkappaB family. The active transcription factor regulates
genes involved in immune, inflammatory and survival responses. Specificity in
gene regulation is achieved, at least in part, by the distinct DNA binding
preferences of the various homo- and heterodimers and by the complex pathways
that lead to signal-induced degradation of the IkappaB inhibitors. Analytical
ultracentrifugation and hydrodynamic bead modelling were used to model the
solution structures of the NFkappaB family member p50, its inhibitor
IkappaBgamma and their complex. Sedimentation equilibrium (SE) and
sedimentation velocity (SV) data show that p50 is a dimer in solution with a
sedimentation coefficient consistent with a conformation intermediate between
the closed conformation observed in the crystal structure of the p50
(N-terminal domain)-p65 heterodimer complexed with IkappaBalpha and the open
conformation adopted by p50 when bound to DNA. SE and SV data show that
IkappaBgamma is a monomer in solution and is prone to aggregation over time.
p50 forms a 2:1 stoichiometric complex with IkappaBgamma in solution with a
sedimentation coefficient consistent with a closed conformation for the p50
dimer.
PMID: 15043934 [PubMed - in process]