Blood, 2010-11, Vol.116 (22), p.4569-4577
2010
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- 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
- Ist Teil von
- Blood, 2010-11, Vol.116 (22), p.4569-4577
- Ort / Verlag
- Washington, DC: Elsevier Inc
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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-XL. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0006-4971, 1528-0020eISSN: 1528-0020DOI: 10.1182/blood-2009-09-245811Titel-ID: cdi_proquest_miscellaneous_1464506724
- Format
- –
- Schlagworte
- Annexin V, Apoptosis - drug effects, bcl-X Protein - genetics, Biological and medical sciences, Bone Marrow Cells - drug effects, Bone Marrow Cells - metabolism, Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors, Cytochromes c - metabolism, Drug Resistance, Neoplasm - drug effects, Extracellular Signal-Regulated MAP Kinases - metabolism, Flavonoids - pharmacology, Gene Expression Regulation, Leukemic - drug effects, Hematologic and hematopoietic diseases, Humans, Interleukin-4 - pharmacology, Interleukin-4 - therapeutic use, Janus Kinase 3 - antagonists & inhibitors, Janus Kinase 3 - metabolism, Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy, Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis, Medical sciences, Myeloid Cell Leukemia Sequence 1 Protein, Phosphorylation - drug effects, Proto-Oncogene Proteins c-bcl-2 - genetics, Pyrimidines - pharmacology, Pyrroles - pharmacology, STAT6 Transcription Factor - metabolism, Stromal Cells - drug effects, Stromal Cells - metabolism, T-Lymphocytes - drug effects, T-Lymphocytes - metabolism, Tumor Cells, Cultured, Tumor Suppressor Protein p53 - metabolism