6-bromoindirubin-3--oxime and Leukemia

6-bromoindirubin-3--oxime has been researched along with Leukemia* in 2 studies

Other Studies

2 other study(ies) available for 6-bromoindirubin-3--oxime and Leukemia

ArticleYear
Glycogen synthase kinase--3β inhibitors suppress leukemia cell growth.
    Experimental hematology, 2010, Volume: 38, Issue:10

    The objective of this study was to investigate the effect of small molecule inhibitors of glycogen synthase kinase-3β (GSK-3β) on leukemia cell growth and survival.. Analysis of cytotoxicity and cell proliferation was conducted using the MTS assay, cell-cycle analysis, and division tracking. Apoptosis was investigated by Annexin-V/7-aminoactinomycin D and caspase-3 expression. The effect of GSK-3β inhibitors was also tested in vivo in an animal model of leukemia. Gene expression analysis was performed to identify the genes modulated by GSK-3β inhibition in leukemia cells.. GSK-3β inhibitors suppress cell growth and induce apoptosis in seven leukemia cell lines of diverse origin, four acute myeloid leukemia, one myelodysplastic syndrome, and one acute lymphoblastic leukemia samples. GSK-3β inhibitors are cytotoxic for rapidly dividing clonogenic leukemia blasts, and higher doses of the inhibitors are needed to eliminate primitive leukemia progenitor/stem cells. Slow cell-division rate, low drug uptake, and interaction with bone marrow stroma make leukemia cells more resistant to apoptosis induced by GSK-3β inhibitors. Global gene expression analysis combined with functional approaches identified multiple genes and specific signaling pathways modulated by GSK-3β inhibition. An important role for Bcl2 in the regulation of apoptosis induced by GSK-3β inhibitors was defined by expression analysis and confirmed by using pharmacological inhibitors of the protein. In vivo administration of GSK-3β inhibitors delayed tumor formation in a mouse leukemia model. GSK-3β inhibitors did not affect hematopoietic recovery following irradiation.. Our data support further evaluation of GSK-3β inhibitors as promising novel agents for therapeutic intervention in leukemia and warrant clinical investigation in leukemia patients.

    Topics: Animals; Apoptosis; Blotting, Western; Cell Line; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Gene Expression Regulation, Leukemic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; HL-60 Cells; Humans; Indoles; Jurkat Cells; K562 Cells; Leukemia; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Oximes; Reverse Transcriptase Polymerase Chain Reaction; U937 Cells; Xenograft Model Antitumor Assays

2010
Glycogen synthase kinase-3beta inhibition preserves hematopoietic stem cell activity and inhibits leukemic cell growth.
    Stem cells (Dayton, Ohio), 2008, Volume: 26, Issue:5

    Ex vivo expansion of cord blood cells generally results in reduced stem cell activity in vivo. Glycogen synthase kinase-3beta (GSK-3beta) regulates the degradation of beta-catenin, a critical regulator of hematopoietic stem cells (HSCs). Here we show that GSK-3beta inhibition activates beta-catenin in cord blood CD34(+) cells and upregulates beta-catenin transcriptional targets c-myc and HoxB4, both known to regulate HSC self-renewal. GSK-3beta inhibition resulted in delayed ex vivo expansion of CD34(+) cells, yet enhanced the preservation of stem cell activity as tested in long-term culture with bone marrow stroma. Delayed cell cycling, reduced apoptosis, and increased adherence of hematopoietic progenitor cells to bone marrow stroma were observed in these long-term cultures treated with GSK-3beta inhibitor. This improved adherence to stroma was mediated via upregulation of CXCR4. In addition, GSK-3beta inhibition preserved severe combined immunodeficiency (SCID) repopulating cells as tested in the nonobese diabetic/SCID mouse model. Our data suggest the involvement of GSK-3beta inhibition in the preservation of HSC and their interaction with the bone marrow environment. Methods for the inhibition of GSK-3beta may be developed for clinical ex vivo expansion of HSC for transplantation. In addition, GSK-3beta inhibition suppressed leukemic cell growth via the induction of apoptosis mediated by the downregulation of survivin. Modulators of GSK-3beta may increase the range of novel drugs that specifically kill leukemic cells while sparing normal stem cells.

    Topics: Animals; Antigens, CD34; beta Catenin; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Cord Blood Stem Cell Transplantation; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hematopoietic Stem Cells; Humans; Indoles; Leukemia; Mice; Mice, SCID; Oximes; Stromal Cells; Time Factors; Umbilical Cord

2008
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