Abstract
Multiple myeloma (MM) is a malignancy characterized by monoclonal paraproteinemia and tissue plasmocytosis. In advanced MM cytopenia and osteopathy may occur. Although several effective treatment strategies have been developed in recent years, there is still a need to identify new drug targets and to develop more effective therapies for patients with advanced MM. We examined the effects of 15 targeted drugs on growth and survival of primary MM cells and 5 MM cell lines (MM.1S, NCI-H929, OPM-2, RPMI-8226, U-266). The PI3-kinase blocker BEZ235, the pan-BCL-2 inhibitor obatoclax, the Hsp90-targeting drug 17AAG, and the Polo-like kinase-1 inhibitor BI2536, were found to exert major growth-inhibitory effects in all 5 MM cell lines tested. Moreover, these drugs suppressed the in vitro proliferation of primary bone marrow-derived MM cells and induced apoptosis at pharmacologic drug concentrations. Apoptosis-inducing effects were not only seen in the bulk of MM cells but also in MM stem cell-containing CD138−/CD20+/CD27+ memory B-cell fractions. Synergistic growth-inhibitory effects were observed in MM cell lines using various drug combinations, including 17AAG+BI2536 in MM.1S, OPM-2, RPMI-8226, and U-266 cells, 17AAG+BEZ235 in MM.1S, OPM-2, RPMI-8226, and U-266 cells, 17AAG+obatoclax in MM.1S, NCI-H929, OPM-2, and RPMI-8226 cells, BI2536+BEZ235 in MM.1S, NCI-H929, OPM-2, and RPMI-8226 cells, BI2536+obatoclax in MM.1S, OPM-2 and RPMI-8226 cells, and BEZ235+obatoclax in MM.1S and RPMI-8226 cells. Together, our data show that various targeted drugs induce profound and often synergistic anti-neoplastic effects in MM cells which may have clinical implications and may contribute to the development of novel treatment strategies in advanced MM.
Highlights
Multiple myeloma (MM) is a hematopoietic neoplasm characterized by an expansion of clonal plasma cells (PC) in the bone marrow (BM) and by an excessive production of monoclonal immunoglobulins (Ig), usually of the IgG- or IgA type [1,2,3]
The histone deacetylase (HDAC)-inhibitor vorinostat suppressed the proliferation of MM.1S, NCI-H929, and U-266 cells (IC50 0.1-1 μM)
Effects of targeted drugs on in vitro proliferation of primary MM cells In a step, we examined the effects of 17AAG, BI2536, BEZ235, and obatoclax on in vitro proliferation of primary neoplastic PC obtained from the BM of patients with MM
Summary
Multiple myeloma (MM) is a hematopoietic neoplasm characterized by an expansion of clonal plasma cells (PC) in the bone marrow (BM) and by an excessive production of monoclonal immunoglobulins (Ig), usually of the IgG- or IgA type [1,2,3]. Survival, and differentiation of MM cells are triggered by various prooncogenic signalling pathways as well as by cytokines and the BM microenvironment [4,5,6,7,8,9]. Depending on their growth-rate and biologic behaviour, MM cells proliferate and expand in the BM and other organs and subsequently cause organ damage [1,2,3,4,5]. In www.impactjournals.com/oncotarget a considerable number of patients, MM develops from a premalignant condition referred to as monoclonal gammopathy of undetermined significance (MGUS) [20]
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