Enhanced CML stem cell elimination in vitro by bryostatin priming with imatinib mesylate

Jorgensen, H.G., Allan, E.K., Mountford, J.C., Richmond, L., Harrison, S., Elliott, M.A. and Holyoake, T.L. (2005) Enhanced CML stem cell elimination in vitro by bryostatin priming with imatinib mesylate. Experimental Hematology, 33(10), pp. 1140-1146. (doi:10.1016/j.exphem.2005.05.020)

Jorgensen, H.G., Allan, E.K., Mountford, J.C., Richmond, L., Harrison, S., Elliott, M.A. and Holyoake, T.L. (2005) Enhanced CML stem cell elimination in vitro by bryostatin priming with imatinib mesylate. Experimental Hematology, 33(10), pp. 1140-1146. (doi:10.1016/j.exphem.2005.05.020)

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Abstract

<p><b>Objective:</b> In chronic myeloid leukemia (CML), imatinib mesylate (IM; Gleevec, Glivec) induces a G0/G1 cell-cycle block in total CD34<sup>+</sup> cells without causing significant apoptosis. Bryostatin-1 (bryo), a protein kinase C (PKC) modulator, was investigated for its ability to increase IM-mediated apoptosis either through induction of cycling of G0/G1 Ph<sup>+</sup> cells or antagonism of the IM-induced cell-cycle block.</p> <p><b>Methods:</b> The Ph<sup>+</sup> K562 cell line and primary CD34<sup>+</sup> CML cells were studied for cell-cycle progression (PI staining), proliferation (311 thymidine uptake), and survival (dye exclusion).</p> <p><b>Results:</b> Following 48 hours exposure to IM, on average more than 80% of surviving K562 cells were in G0/G1 as compared to approximately 50% for untreated control cultures (p < 0.001). After accounting for IM-induced cell kill, the absolute number of viable G0/G1 cells was significantly increased, confirming its anti-proliferative effect. However, pretreatment for 24 hours with bryo both increased K562 total cell kill and normalized the percentage of cells recovered in G0/G1, thus reducing their absolute number. For primary CML CD34<sup>+</sup> cells, pretreatment with bryo prior to IM significantly enhanced cell death of both total and, critically, G0/G1 populations.</p> <p><b>Conclusion:</b> These results suggest that carefully scheduled drug combinations that include an agent to antagonize the anti-proliferative effect of IM may prove more efficacious within the Ph+ stem cell compartment than IM monotherapy.</p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Mountford, Dr Joanne and Harrison, Mr Simon and Allan, Mrs Elaine and Jorgensen, Dr Heather
Authors: Jorgensen, H.G., Allan, E.K., Mountford, J.C., Richmond, L., Harrison, S., Elliott, M.A., and Holyoake, T.L.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Experimental Hematology
ISSN:0301-472X

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