title: Inhibition of nuclear factor-kappaB suppresses peritoneal dissemination of gastric cancer by blocking cancer cell adhesion.
abstract: Currently, patients with peritoneal dissemination of gastric cancer must accept a poor prognosis because there is no standard effective therapy. To inhibit peritoneal dissemination it is important to inhibit interactions between extracellular matrices (ECM) and cell surface integrins, which are important for cancer cell adhesion. Although nuclear factor-kappa B (NF-κB) is involved in various processes in cancer progression, its involvement in the expression of integrins has not been elucidated. We used a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), to study whether NF-κB blocks cancer cell adhesion via integrins in a gastric cancer dissemination model in mice and found that DHMEQ is a potent suppressor of cancer cell dissemination. Dehydroxymethylepoxyquinomicin suppressed the NF-κB activity of human gastric cancer cells NUGC-4 and 44As3Luc and blocked the adhesion of cancer cells to ECM when compared with the control. Dehydroxymethylepoxyquinomicin also inhibited expression of integrin (α2, α3, β1) in in vitro studies. In the in vivo model, we injected 44As3Luc cells pretreated with DHMEQ into the peritoneal cavity of mice and performed peritoneal lavage after the injection of cancer cells. Viable cancer cells in the peritoneal cavities were evaluated sequentially by in vivo imaging. In mice injected with DHMEQ-pretreated cells and lavaged, live cancer cells in the peritoneum were significantly reduced compared with the control, and these mice survived longer. These results indicate that DHMEQ could inhibit cancer cell adhesion to the peritoneum possibly by suppressing integrin expression. Nuclear factor-kappa B inhibition may be a new therapeutic option for suppressing postoperative cancer dissemination.
authors.affiliation: Department of General Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mino
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Sanae
authors.initials: S
authors.lastname: Haga
authors.forename: Masanori
authors.initials: M
authors.lastname: Sato
authors.forename: Masaya
authors.initials: M
authors.lastname: Kina
authors.forename: Masato
authors.initials: M
authors.lastname: Takahashi
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takahashi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kataoka
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.forename: Toshiya
authors.initials: T
authors.lastname: Kamiyama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D002469:Cell Separation; D003512:Cyclohexanones / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000517:prevention & control / Q000556:secondary; D013274:Stomach Neoplasms / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin