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Exp Hematol. 2010 Oct;38(10):908-921.e1. doi: 10.1016/j.exphem.2010.06.001. Epub 2010 Jun 9.

Glycogen synthase kinase--3β inhibitors suppress leukemia cell growth.

Author information

1
Sydney Cord and Marrow Transplant Facility, Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Sydney, Australia.

Abstract

OBJECTIVE:

The objective of this study was to investigate the effect of small molecule inhibitors of glycogen synthase kinase-3β (GSK-3β) on leukemia cell growth and survival.

MATERIALS AND METHODS:

Analysis of cytotoxicity and cell proliferation was conducted using the MTS assay, cell-cycle analysis, and division tracking. Apoptosis was investigated by Annexin-V/7-aminoactinomycin D and caspase-3 expression. The effect of GSK-3β inhibitors was also tested in vivo in an animal model of leukemia. Gene expression analysis was performed to identify the genes modulated by GSK-3β inhibition in leukemia cells.

RESULTS:

GSK-3β inhibitors suppress cell growth and induce apoptosis in seven leukemia cell lines of diverse origin, four acute myeloid leukemia, one myelodysplastic syndrome, and one acute lymphoblastic leukemia samples. GSK-3β inhibitors are cytotoxic for rapidly dividing clonogenic leukemia blasts, and higher doses of the inhibitors are needed to eliminate primitive leukemia progenitor/stem cells. Slow cell-division rate, low drug uptake, and interaction with bone marrow stroma make leukemia cells more resistant to apoptosis induced by GSK-3β inhibitors. Global gene expression analysis combined with functional approaches identified multiple genes and specific signaling pathways modulated by GSK-3β inhibition. An important role for Bcl2 in the regulation of apoptosis induced by GSK-3β inhibitors was defined by expression analysis and confirmed by using pharmacological inhibitors of the protein. In vivo administration of GSK-3β inhibitors delayed tumor formation in a mouse leukemia model. GSK-3β inhibitors did not affect hematopoietic recovery following irradiation.

CONCLUSIONS:

Our data support further evaluation of GSK-3β inhibitors as promising novel agents for therapeutic intervention in leukemia and warrant clinical investigation in leukemia patients.

PMID:
20540984
DOI:
10.1016/j.exphem.2010.06.001
[Indexed for MEDLINE]

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