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      FoxM1 Is a General Target for Proteasome Inhibitors

      research-article
      1 , 1 , 2 , 1 , 2 , 3 , *
      PLoS ONE
      Public Library of Science

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          Abstract

          Proteasome inhibitors are currently in the clinic or in clinical trials, but the mechanism of their anticancer activity is not completely understood. The oncogenic transcription factor FoxM1 is one of the most overexpressed genes in human tumors, while its expression is usually halted in normal non-proliferating cells. Previously, we established that thiazole antibiotics Siomycin A and thiostrepton inhibit FoxM1 and induce apoptosis in human cancer cells. Here, we report that Siomycin A and thiostrepton stabilize the expression of a variety of proteins, such as p21, Mcl-1, p53 and hdm-2 and also act as proteasome inhibitors in vitro. More importantly, we also found that well-known proteasome inhibitors such as MG115, MG132 and bortezomib inhibit FoxM1 transcriptional activity and FoxM1 expression. In addition, overexpression of FoxM1 specifically protects against bortezomib-, but not doxorubicin-induced apoptosis. These data suggest that negative regulation of FoxM1 by proteasome inhibitors is a general feature of these drugs and it may contribute to their anticancer properties.

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          Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls.

          Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.
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            Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs.

            The cytotoxicity of chemotherapeutic agents is attributed to apoptosis. Acquired resistance to the effects of chemotherapy has emerged as a significant impediment to effective cancer therapy. One feature that cytotoxic treatments of cancer have in common is their activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which regulates cell survival. NF-kappaB activation suppresses the apoptotic potential of chemotherapeutic agents and contributes to resistance. What evidence is there that inhibitors of NF-kappaB might promote apoptosis in cancer cells and can NF-kappaB inhibitors be used to overcome resistance to chemotherapeutic agents?
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              Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib.

              The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2009
                12 August 2009
                : 4
                : 8
                : e6593
                Affiliations
                [1 ]Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America
                [2 ]Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America
                [3 ]Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois, United States of America
                Dresden University of Technology, Germany
                Author notes

                Conceived and designed the experiments: AG. Performed the experiments: UGB MH. Analyzed the data: UGB MH AG. Contributed reagents/materials/analysis tools: AG. Wrote the paper: AG.

                Article
                08-PONE-RA-07219R7-A
                10.1371/journal.pone.0006593
                2721658
                19672316
                a0921437-6233-4c23-ba61-97d5e293ee91
                Bhat et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 6 November 2008
                : 9 July 2009
                Page count
                Pages: 5
                Categories
                Research Article
                Oncology
                Oncology/Myeloproliferative Disorders, including Chronic Myeloid Leukemia
                Oncology/Oncology Agents

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                Uncategorized

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