Inhibition of inhibitor of nuclear factor-kappaB phosphorylation increases the efficacy of paclitaxel in in vitro and in vivo ovarian cancer models
| Autor: | Hirohisa Kurachi, Yuji Murata, Namiko Yada-Hashimoto, Seiji Mabuchi, Kazuhiro Takahashi, Keiichi Tasaka, Jun Kawagoe, Hozumi Seino-Noda, Masahide Ohmichi, Tadashi Hayasaka, Joseph R. Testa, Tsuyoshi Ohta, Yukihiro Nishio, Akiko Kimura, Masahiro Sakata, Teiichi Motoyama |
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| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
Time Factors IκB kinase environment and public health Wortmannin chemistry.chemical_compound Mice Phosphatidylinositol 3-Kinases Anti-Infective Agents Medicine LY294002 Sulfones Enzyme Inhibitors Phosphorylation Ovarian Neoplasms NF-kappa B Drug Synergism I-kappa B Kinase Drug Combinations Oncology Paclitaxel Female Proteoglycans Collagen Plasmids Signal Transduction Transcriptional Activation medicine.medical_specialty Morpholines Blotting Western Mice Nude Antineoplastic Agents Protein Serine-Threonine Kinases Internal medicine Cell Line Tumor Nitriles Animals Humans Phosphatidylinositol Protein kinase B Cell Proliferation Dose-Response Relationship Drug business.industry I-Kappa-B Kinase Antineoplastic Agents Phytogenic Androstadienes Endocrinology chemistry Chromones Cancer research Laminin business |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 10(22) |
| ISSN: | 1078-0432 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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