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

To: Icebrg who wrote (1749)	8/3/2003 3:06:22 PM
From: Icebrg	Read Replies (2) \| Respond to of 3044

Blood. 2003 Jul 31 The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. Interactions between the proteasome inhibitor bortezomib (Velcade(TM) (previously known as PS-341) and histone deacetylease inhibitors (HDIs) have been examined in Bcr/Abl(+) human leukemia cells (K562 and LAMA 84). Co-exposure of cells (24-48hr) to minimally toxic concentrations of bortezimib + either SAHA or sodium butyrate (SB) resulted in a striking increase in mitochondrial injury, caspase activation, and apoptosis, reflected by caspase-3 and -8 cleavage and PARP degradation. These events were accompanied by down-regulation of the Raf-1/MEK/ERK pathway as well as diminished expression of Bcr/Abl and cyclin D1, cleavage of p21(CIP1) and pRb, and induction of the stress-related kinases JNK and p38 MAPK. Transient transfection of cells with a constitutively active MEK construct significantly protected them from bortezimib /SAHA-mediated lethality. Co-administration of bortezimib and SAHA resulted in increased ROS generation and diminished NF-kappaB activation; moreover, the free radical scavenger L-N-acetylcyteine (LNAC) blocked bortezimib /SAHA-related ROS generation, induction of JNK and p21(CIP1), and apoptosis. Lastly, this regimen potently induced apoptosis in STI571 (imatinib mesylate)-resistant K562 cells and CD34(+) mononuclear cells obtained from a patient with STI571-resistant disease, as well as in Bcr/Abl(-) leukemia cells (e.g., HL-60, U937, Jurkat). Together, these findings raise the possibility that combined proteasome/histone deacetylase inhibition may represent a novel strategy in leukemia, including apoptosis-resistant Bcr/Abl(+) hematologic malignancies. [I wonder if they are cheering at Titan?]