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
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.
4569-77
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Prentice, Archibald G.
a834a471-b816-4c3a-a3d4-70fa8dd2c982
Cwynarski, Kate
34d6aef4-8106-40ee-9609-b44460ccb971
Hoffbrand, A. Victor
f33e01e3-5c17-40fd-b66d-155e4f3bbffe
Hart, Stephen M.
43396380-899f-44e0-86c3-3aa10aae993c
Lowdell, Mark W.
399d3d5b-dcd3-4b23-a6f9-7141c0717f56
Samuel, Edward R.
33ab7fcf-e1fe-455b-8a7e-24f641ef903b
Wickremasinghe, R. Gitendra
6a90cc2b-8db5-45c2-ab57-7a1341b88bb2
25 November 2010
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Prentice, Archibald G.
a834a471-b816-4c3a-a3d4-70fa8dd2c982
Cwynarski, Kate
34d6aef4-8106-40ee-9609-b44460ccb971
Hoffbrand, A. Victor
f33e01e3-5c17-40fd-b66d-155e4f3bbffe
Hart, Stephen M.
43396380-899f-44e0-86c3-3aa10aae993c
Lowdell, Mark W.
399d3d5b-dcd3-4b23-a6f9-7141c0717f56
Samuel, Edward R.
33ab7fcf-e1fe-455b-8a7e-24f641ef903b
Wickremasinghe, R. Gitendra
6a90cc2b-8db5-45c2-ab57-7a1341b88bb2
Steele, Andrew J., Prentice, Archibald G., Cwynarski, Kate, Hoffbrand, A. Victor, Hart, Stephen M., Lowdell, Mark W., Samuel, Edward R. and Wickremasinghe, R. Gitendra
(2010)
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, 116 (22), .
(doi:10.1182/blood-2009-09-245811).
(PMID:20716767)
Abstract
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.
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Published date: 25 November 2010
Organisations:
Cancer Sciences
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Local EPrints ID: 178119
URI: http://eprints.soton.ac.uk/id/eprint/178119
ISSN: 0006-4971
PURE UUID: 36d59d5a-ed8f-43ba-be45-1738cb06d14b
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Date deposited: 23 Mar 2011 10:03
Last modified: 14 Mar 2024 02:57
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Author:
Archibald G. Prentice
Author:
Kate Cwynarski
Author:
A. Victor Hoffbrand
Author:
Stephen M. Hart
Author:
Mark W. Lowdell
Author:
Edward R. Samuel
Author:
R. Gitendra Wickremasinghe
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