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)

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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 > School of Psychology & Neuroscience
Journal Name:Experimental Hematology
ISSN:0301-472X

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