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.
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.
Steele
Andrew J
AJ
Department of Hematology, Cancer Institute, University College Medical School, London, UK.
Prentice
Archibald G
AG
Cwynarski
Kate
K
Hoffbrand
A Victor
AV
Hart
Stephen M
SM
Lowdell
Mark W
MW
Samuel
Edward R
ER
Wickremasinghe
R Gitendra
RG
D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology / Q000627:therapeutic use*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D050800:STAT6 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics
D005419:Flavonoids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C554945:PF 956980; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011758:Pyrroles; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D015847:Interleukin-4; D045304:Cytochromes c; D053616:Janus Kinase 3; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one