Abstract 5044: Dual GSK-3β/CDK inhibitors induce multiple myeloma cell death and eliminate putative cancer stem cell populations

Abstract

Abstract Multiple myeloma (MM) is a plasma cell malignancy that recurs in 100% of patients despite high treatment response rates. The incurable nature of the disease and the low proliferative capacity of terminally differentiated MM plasma cells supports the existence of a cancer stem cell (CSC) component - a cell population with self-renewal and drug resistance properties capable of repopulating the disease after seemingly effective treatment and periods of undetectable disease. It is imperative to develop new therapies that target both terminally differentiated MM plasma cells and MM CSCs to extend disease-free survival and control the disease. We tested the ability of c-Myc-inducing compounds, such as GSK-3β and dual GSK-3β/CDK inhibitors, to enhance the activity of bortezomib against advanced MM cell lines (RPM-I8226 and NCI-H929). We have shown that this class of inhibitors has anti-tumor effects and sensitizes numerous solid malignancies to apoptosis-inducing agents (Mayes P.A., Dolloff N.G. et al., in revision). Moreover, c-Myc expression increases protein translation, and in doing so, enhances the cytotoxicity of proteasome inhibitors such as bortezomib (Nawrocki et al., 2008). We found that GSK-3β inhibitors (lithium choloride and sc-24020) failed to induce apoptosis or reduce viability of MM cell lines or to enhance the activity of bortezomib. By contrast, the dual GSK-3β/CDK inhibitors, alsterpaullone and the nucleoside analogue SLM3 (Mayes P.A., Dolloff, N.G. et al., in revision), were highly toxic to MM cells both alone and in combination with bortezomib. In addition to inducing massive apoptosis and reducing MM cell viability, alsterpaullone and SLM3 eliminated the presence of dye-effluxing side-populations, that have been shown to exhibit CSC behavior in vitro and in animal models of MM. By comparison, bortezomib, adriamycin and melphalan increased the percentage of MM side-population cells, suggesting that MM CSC cells are more resistant to these agents compared to their non-CSC counterparts. Interestingly, alsterpaullone and SLM3 eliminate a distinctly large sub-population of MM cells that are enriched in side-population cells, providing a further characterization of the MM CSC phenotype. We propose that using GSK-3β/CDK inhibitors may be effective therapies, as they target tumorigenic CSC populations, which are responsible for disease relapse. We are currently testing this hypothesis in mouse models of MM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5044.