Antimyeloma Effects of the Heat Shock Protein 70 Molecular Chaperone Inhibitor MAL3-101
Figure 3
MAL3-101 and MG-132 exhibit synergistic, cytotoxic effects on multiple myeloma tumor cells and endothelial progenitor cells. (a) NCI-H929 cells () were exposed to the indicated concentrations of MAL3-101, MG-132, or a combination of these agents for 40 h, and survival was assessed by an MTS assay; representative data from one of seven independent experiments are shown; error bars represent SDs from replicate data points. Apparent absence of error bars indicates minimal variance. (b) The fraction of nonviable cells compared to control, DMSO-treated cells in this experiment was used for isobologram analysis. In brief, the cellular fraction affected (Fa) was calculated based on the indicated MTS assays using the following formula: minus the percent of viable cells. Fa values at the indicated drug concentrations were used by CalcuSyn to derive combination index (CI) values, where indicates additive effects, indicates synergy, and indicates antagonism [14]. (c) Bone-marrow-derived tumor cells (black bars) and confluent endothelial progenitor cells (EPCs) (white bars) from multiple myeloma patients were exposed to the indicated concentrations of MAL3-101, MG-132, or their combination, and survival was assessed by an MTS assay. Dunnett’s test, after significant one-way repeated-measures analyses of variance ( and 0.002 for tumor cells and EPCs, resp.), compared control values to cell viability in cultures treated with MAL3-101, MG-132, or MAL3-101 + MG-132 (*, **). (d) Normal peripheral blood mononuclear cells (PBMCs, black bars), bone marrow mononuclear cells (BMMCs, gray bars), and confluent bone-marrow-derived EPCs (white bars) were exposed to the indicated concentrations of MAL3-101, MG-132, or a combination of these agents, and survival was assessed by an MTS assay.
