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With this report, we now show that enzastaurin exhibits direct antitumor activity, inducing tumor cell apoptosis and suppressing tumor cell proliferation. Moreover, enzastaurin interferes with signaling through the AKT pathway, a pathway frequently activated in a variety of human cancers.The biology and clinical relevance of the PTEN tumor suppressor pathway.Int J Biochem Cell Biol. Sp is involved in Aktmediated induction of VEGF expression through an HIFindependent mechanism.Vascular endothelial growth factor transcriptional activation is mediated by hypoxiainducible factor a, HDM, and pSK in response to phosphatidylinositol kinaseAKT signaling.Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from on April. American Association for Cancer Research. Paclitaxel also caused a transient increase in NFB activity, followed by a decrease in NFB activity.Inhibition of NFB activity by treatment with an IB phosphorylation inhibitor attenuated both basal and transient induction of IB phosphorylation by paclitaxel.Treatment with BAY also enhanced the inhibition of NFB activity by paclitaxel for up to hours.In addition, treatment with BAY decreased the viability of cells treated with paclitaxel.The costs of publication of this article were defrayed in part by the payment of page charges.Unlike other antimicrotubule agents that interfere with tubulin polymerization, paclitaxel increases tubulin polymerization, stabilizes microtubules, and prevents tubulin depolymerization, ultimately causing tubulin bundling. These effects of the drug are associated with cell cycle arrest in GM phase of the cell cycle, as well as cellular toxicity. The inclusion of paclitaxel in the treatment of patients with newly diagnosed ovarian cancer has led to improved response rates and prolonged median survival compared with the results of prior therapeutic regimens. Nevertheless, most of patients with advanced ovarian cancer are destined to relapse and develop resistance to initially active drugs such as paclitaxel. The sensitivity of cells to chemotherapeutic druginduced apoptosis seems to depend on the balance between proapoptotic and antiapoptotic signals.NFB is activated in certain cancers and in response to chemotherapy and radiation.NFB normally resides in the cytoplasm as an inactivated form in a Isoborneol complex with inhibitor of NFB. Although it was proposed that NFB might be required for paclitaxelinduced cell death, most reports suggest that paclitaxelinduced NFB activity mediates survival signals that counteract apoptosis. It has been reported that intrinsically or constitutively activated NFB may be critical in the development of drug resistance in cancer cells. Therefore, several agents that are able to inhibit NFB function might be considered as an adjuvant approach in combination with paclitaxel for lung cancer. These considerations led us to examine whether the status of NFB activity is involved in the sensitivity to paclitaxel in human ovarian cancer cells and whether agents that are able to inhibit NFB function might be considered as an adjuvant approach in combination with paclitaxel for ovarian cancer.In the present study, we show that BAY, a known pharmacologic inhibitor of IB phosphorylation, inhibits both basal and transient induction of IB phosphorylation and NFB activity by paclitaxel for hours.The cells were cultured at C in DMEM with fetal bovine serum in a watersaturated atmosphere of air and CO.

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