title: Inhibition of inhibitor of nuclear factor-kappaB phosphorylation increases the efficacy of paclitaxel in in vitro and in vivo ovarian cancer models.
abstract: We investigated whether inhibition of nuclear factor-kappaB (NFkappaB) increases the efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Treatment of paclitaxel-sensitive Caov-3 cells with paclitaxel transiently activated the phosphorylation of Akt, the phosphorylation of IkappaB kinase (IKK), and the phosphorylation of inhibitor of NFkappaB (IkappaBalpha). Paclitaxel also caused a transient increase in NFkappaB activity, followed by a decrease in NFkappaB activity. We show an association between Akt and IKK and show that the phosphorylation of IKK induced by paclitaxel is blocked by treatment with a phosphatidylinositol 3-kinase inhibitor (wortmannin or LY294002). Furthermore, interference of the Akt signaling cascade inhibits the transient induction of IkappaBalpha phosphorylation and NFkappaB activity by paclitaxel. Inhibition of NFkappaB activity by treatment with an IkappaBalpha phosphorylation inhibitor (BAY 11-7085) attenuated both basal and transient induction of IkappaBalpha phosphorylation by paclitaxel. Treatment with BAY 11-7085 also enhanced the inhibition of NFkappaB activity by paclitaxel for up to 24 hours. In addition, treatment with BAY 11-7085 decreased the viability of cells treated with paclitaxel. Moreover, treatment with BAY 11-7085 increased the efficacy of paclitaxel-induced inhibition of intraabdominal dissemination and production of ascites in athymic nude mice inoculated intraperitoneally with Caov-3 cells. These results suggest that paclitaxel transiently induces NFkappaB activity via the phosphatidylinositol 3-kinase/Akt cascade and that combination therapy with paclitaxel and an NFkappaB inhibitor would increase the therapeutic efficacy of paclitaxel.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Medical School, Osaka, 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: 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: Hozumi
authors.initials: H
authors.lastname: Seino-Noda
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: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tasaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Murata
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000494:pharmacology; D015398:Signal Transduction; D013450:Sulfones; D013997:Time Factors; D015533:Transcriptional Activation; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002867:Chromones; D003094:Collagen; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D051550:I-kappa B Kinase; D007797:Laminin; D009025:Morpholines; D016328:NF-kappa B; D009570:Nitriles; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D013450:Sulfones; D000077191:Wortmannin; C416282:BAY 11-7085; C059485:matrigel; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496559:CHUK protein, human; C496564:Chuk protein, mouse; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse