Modulating Glycogen Synthase Kinase-3 in Chronic Lymphocytic Leukemia
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Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in North America and Europe with a median age of onset of 72. Due to the advanced age of most patients with CLL, many are unable to tolerate standard treatments and receive sub-optimal care. Despite the availability of various treatment options, CLL remains incurable. Glycogen synthase kinase-3 (GSK-3) is a metabolic enzyme dysregulated in CLL. It has two isoforms: GSK-3α and β. Our hypothesis is that GSK-3 is a critical enzyme for CLL cell survival and therefore a target that can be exploited for therapeutic benefit. In this study the effect of chemical pan-inhibition of GSK-3 is characterized using lithium chloride and SB216763 (SB) in CLL- like cell lines. Pan inhibition with LiCl and SB causes a decrease in cell viability after 48 and 72 hours of treatment with β-catenin stabilization. Secondly, isoform-specific loss of GSK- 3α and β by RNA interference is confirmed in CLL-like cell lines. Loss of either isoform alone did not result in β-catenin stabilization. Finally, phenotypic effects of novel pan- and isoformselective GSK-3 inhibitors are characterized in primary CLL cells. The Broad Institute of MIT and Harvard supplied five novel inhibitory compounds including two pan inhibitors, one GSK-3β inhibitor and two GSK-3α inhibitors. Only the pan- and GSK-3β inhibitors reduced viability in a dose- and time-dependent manner. However, β-catenin stabilization was also dose-dependent. These findings question isoform selectivity of the novel compounds tested and suggest that further studies are required to fully characterize their on and off target effects.
glycogen synthase kinase-3, chronic lymphocytic leukemia