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Biotech / Medical : Millennium Pharmaceuticals, Inc. (MLNM) -- Ignore unavailable to you. Want to Upgrade?

To: Icebrg who wrote (2126)	6/7/2004 4:12:00 PM
From: Icebrg	Read Replies (3) \| Respond to of 3044

Combined proteasome and histone deacetylase inhibition in non–small cell lung cancer Chadrick E. Denlinger, MDa, Michael D. Keller, BSb, Marty W. Mayo, PhDa,b, R. Michael Broad, PhDa, David R. Jones, MD,a [Yet another study indicating a potential synergy between Velcade and HDAC inhibitors. Maybe Millennium should speak to Titan about Pivanex, which is a butyric acid derivative]. Thorac Cardiovasc Surg 2004;127:1078-1086 a Department of Surgery, Charlottesville, Va, USA b Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Va, USA Read in part at the American Association of Thoracic Surgery, Boston, Mass, May 2003. Received for publication May 2, 2003; revisions received June 10, 2003; revisions received July 4, 2003; accepted for publication July 10, 2003. Address for reprints: David R. Jones, MD, Thoracic and Cardiovascular Surgery, University of Virginia, Charlottesville, VA 22908-0679, USA djones@virginia.edu OBJECTIVE: Inhibitors of histone deacetylases are potent inducers of cell-cycle arrest and apoptosis in certain malignancies. We have previously demonstrated that chemotherapy activates the antiapoptotic transcription factor nuclear factor B in non–small cell lung cancer and fails to induce significant levels of apoptosis. We hypothesize that nuclear factor B inhibition with the proteasome inhibitor bortezomib (formerly known as PS-341) will sensitize non–small cell lung cancer cells to histone deacetylase inhibitor–mediated apoptosis. METHODS: Tumorigenic non–small cell lung cancer cells (A549, H358, and H460) were treated with bortezomib, followed by the histone deactylase inhibitor sodium butyrate. After treatment, nuclear factor B transcriptional activity was measured by using a luciferase reporter assay and transcription of the nuclear factor B–dependent gene IL8. Apoptosis was determined on the basis of caspase-3 activation and DNA fragmentation. Western blot analyses for the cell-cycle regulatory proteins p21 and p53 were performed, and cell-cycle alterations were determined by means of FACS analysis. Experiments were performed in triplicate, and statistical significance was determined by using unpaired t tests. RESULTS: Butyrate increased nuclear factor B transcriptional activity 4-fold relative to that seen in control cells (P = .05) in all non–small cell lung cancer cell lines. Treatment with bortezomib reduced butyrate-induced activation of nuclear factor B to baseline levels. The proteins p21 and p53 were stabilized after treatment with bortezomib, correlating with a G2/M cell-cycle arrest. Treatment with butyrate alone resulted in minimal apoptosis, but combined histone deacetylase and proteasome inhibition increased apoptosis 3- to 4-fold (P = .02). CONCLUSIONS: Combined molecular targeting of histone deacteylases and proteasomes synergistically induced apoptosis in non–small cell lung cancer. Pharmacologic nuclear factor B suppression through proteasome inhibition, followed by treatment with histone deacetylase inhibitors, might represent a novel treatment strategy for patients with non–small cell lung cancer.

To: Icebrg who wrote (2126)	1/22/2006 2:58:21 PM
From: tuck	Read Replies (1) \| Respond to of 3044

[Velcade & HDAC inhibitor FK228 versus leukemia] >>Acta Haematol. 2006;115(1-2):78-90. Histone Deacetylase Inhibitor Depsipeptide (FK228) Induces Apoptosis in Leukemic Cells by Facilitating Mitochondrial Translocation of Bax, Which Is Enhanced by the Proteasome Inhibitor Bortezomib. Sutheesophon K, Kobayashi Y, Takatoku MA, Ozawa K, Kano Y, Ishii H, Furukawa Y. Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan. Histone deacetylase (HDAC) inhibitors are promising candidates for molecular-targeted therapy for leukemia. In this study, we investigated the mechanisms of cytotoxic effects of depsipeptide (FK228), one of the most effective HDAC inhibitors against leukemia, using human myeloid leukemic cell lines HL-60 and K562. We found that FK228 activated caspase-9 and a subsequent caspase cascade by perturbing the mitochondrial membrane to release cytochrome c, which was almost completely blocked by overexpression of Bcl-2. The mitochondrial damage was caused by the translocation of Bax but not other pro-apoptotic Bcl-2 family proteins to the mitochondria. FK228 did not affect the interaction between Bax and Bax adaptor proteins such as 14-3-3theta and Ku70. FK228-induced apoptosis and mitochondrial translocation of Bax were markedly enhanced by the proteasome inhibitor bortezomib. The synergistic action of FK228 and bortezomib was at least partly mediated through conformational changes in Bax, which facilitate its translocation to the mitochondria. These results suggest that the combination of HDAC inhibitors and proteasome inhibitors is useful in the treatment of leukemia especially in the context of molecular-targeted therapy. The status of Bcl-2 and Bax may influence the sensitivity of tumors to this combination and thus can be a target of further therapeutic intervention.<< Cheers, Tuck