Whether or not inhibition of NFkappaB increases the efficacy of
cisplatin in in vitro and in vivo
ovarian cancer models was investigated. We compared the basal levels of phosphorylation of
IkappaBalpha and activity of NFkappaB between
cisplatin-sensitive A2780 cells and
cisplatin-resistant Caov-3 cells. The basal levels of phosphorylation of
IkappaBalpha and activity of NFkappaB in Caov-3 cells were significantly higher than those in A2780 cells.
Cisplatin caused a more marked decrease in the phosphorylation of
IkappaBalpha and activity of NFkappaB in A2780 cells than in Caov-3 cells. Thus, high basal levels of phosphorylation of
IkappaBalpha and activation of NFkappaB and less marked inhibition of the phosphorylation of
IkappaBalpha and activation of NFkappaB by
cisplatin seem to reduce the sensitivity of cells to
cisplatin. Inhibition of NFkappaB activity either by treatment with the
IkappaBalpha phosphorylation inhibitor (BAY 11-7085) or a specific NFkappaB nuclear translocation inhibitor (SN-50) or by transfection of p50DeltaNLS (which lacks the
nuclear localization signal domain) increased the efficacy of both the
cisplatin-induced attenuation of
IkappaBalpha phosphorylation and NFkappaB 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
X-linked inhibitor of apoptosis protein (XIAP) and cell invasion through
Matrigel. Moreover, treatment with
BAY 11-7085 increased the efficacy of the
cisplatin-induced inhibition of the intra-abdominal dissemination and production of
ascites using athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that combination
therapy of
cisplatin with the NFkappaB inhibitor should increase the therapeutic efficacy of
cisplatin.