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Inhibition of Inhibitor of Nuclear Factor-B Phosphorylation Increases the Efficacy of Paclitaxel in in Vitro and in Vivo Ovarian Cancer Models

¹ Department of Obstetrics and Gynecology, Osaka University Medical School, Osaka, Japan; Departments of ² Obstetrics and Gynecology and ³ Pathology, Yamagata University, School of Medicine, Yamagata, Japan; and ⁴ Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania

We investigated whether inhibition of nuclear factor-B (NFB) 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 IB kinase (IKK), and the phosphorylation of inhibitor of NFB (IB). Paclitaxel also caused a transient increase in NFB activity, followed by a decrease in NFB 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 IB phosphorylation and NFB activity by paclitaxel. Inhibition of NFB activity by treatment with an IB phosphorylation inhibitor (BAY 11-7085) attenuated both basal and transient induction of IB phosphorylation by paclitaxel. Treatment with BAY 11-7085 also enhanced the inhibition of NFB 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 NFB activity via the phosphatidylinositol 3-kinase/Akt cascade and that combination therapy with paclitaxel and an NFB inhibitor would increase the therapeutic efficacy of paclitaxel.

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