Inhibition of NFkappaB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models.
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.
Mabuchi
Seiji
S
Department of Obstetrics and Gynecology, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
Ohmichi
Masahide
M
Nishio
Yukihiro
Y
Hayasaka
Tadashi
T
Kimura
Akiko
A
Ohta
Tsuyoshi
T
Saito
Maki
M
Kawagoe
Jun
J
Takahashi
Kazuhiro
K
Yada-Hashimoto
Namiko
N
Sakata
Masahiro
M
Motoyama
Teiichi
T
Kurachi
Hirohisa
H
Tasaka
Keiichi
K
Murata
Yuji
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation
D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D002945:Cisplatin