title: Inhibition of NFkappaB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Mabuchi
authors.forename: Masahide
authors.initials: M
authors.lastname: Ohmichi
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Nishio
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hayasaka
authors.forename: Akiko
authors.initials: A
authors.lastname: Kimura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ohta
authors.forename: Maki
authors.initials: M
authors.lastname: Saito
authors.forename: Jun
authors.initials: J
authors.lastname: Kawagoe
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Namiko
authors.initials: N
authors.lastname: Yada-Hashimoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakata
authors.forename: Teiichi
authors.initials: T
authors.lastname: Motoyama
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kurachi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tasaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Murata
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D002945:Cisplatin