pf-956980 and Leukemia--Lymphocytic--Chronic--B-Cell

pf-956980 has been researched along with Leukemia--Lymphocytic--Chronic--B-Cell* in 1 studies

Other Studies

1 other study(ies) available for pf-956980 and Leukemia--Lymphocytic--Chronic--B-Cell

ArticleYear
The JAK3-selective inhibitor PF-956980 reverses the resistance to cytotoxic agents induced by interleukin-4 treatment of chronic lymphocytic leukemia cells: potential for reversal of cytoprotection by the microenvironment.
    Blood, 2010, Nov-25, Volume: 116, Issue:22

    Extensive evidence suggests that the malignant cells of chronic lymphocytic leukemia (CLL) patients are in close contact with activated T lymphocytes, which secrete a range of cytoprotective cytokines including interleukin-4 (IL-4). IL-4 induced the rapid phosphorylation and activation of the signal transducer and activator of transcription 6 transcription factor in CLL cells in vitro. Longer incubation with IL-4 resulted in up-regulation of the antiapoptotic proteins, Mcl-1 and Bcl-X(L). All of these events were blocked by the JAK3-selective inhibitor, PF-956980. A dye reduction cytotoxicity assay showed that IL-4 induced resistance to the cytotoxic drugs fludarabine and chlorambucil and to the novel p53-elevating agent nutlin 3. IL-4-induced drug resistance was reversed by PF-956980. These conclusions were confirmed by independent assays for apoptosis induction (annexin V binding, cleavage of poly[ADP-ribose] polymerase, and morphologic analysis). Coculture with bone marrow stromal cells in the presence of supernatants derived from activated T-lymphocyte cultures also protected CLL cells from apoptosis induction by chlorambucil. Protection by these combined signals was reversed by PF-956980. The data here provide a preclinical rationale for the possible therapeutic use of PF-956980 in conjunction with conventional cytotoxic drugs to achieve more extensive killing of CLL cells by overcoming antiapoptotic signaling by the microenvironment.

    Topics: Apoptosis; bcl-X Protein; Bone Marrow Cells; Calcium-Calmodulin-Dependent Protein Kinases; Cytochromes c; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Gene Expression Regulation, Leukemic; Humans; Interleukin-4; Janus Kinase 3; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Pyrroles; STAT6 Transcription Factor; Stromal Cells; T-Lymphocytes; Tumor Cells, Cultured; Tumor Suppressor Protein p53

2010