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. 2021 Feb 17;13(4):843. doi: 10.3390/cancers13040843

Figure 4.

Figure 4

Figure 4

Additive and synergistic effects of LonP1 and proteasome inhibitors: (A) Determination of the cytotoxic range of the LonP1 inhibitor CDDO-Me in MM.1S cells in acute toxicity assays (24 h treatment). We used the more potent methyl-ester derivative of CDDO (CDDO-Me) in all experiments. Concentrations of up to 300 nM had no toxic effect as measured by XTT assay (shown here) and by acridine orange and propidium iodide staining (not shown). The individual data points indicate averages and the error bars standard deviations. Applying the LonP1-specific inhibitor CDDO-Me at sublethal concentrations (300 nM) in MM.1S cells strongly increased the cytotoxic effect of carfilzomib, but only mildly increased the effect of bortezomib; (B) Isobologram analysis indicates synergy between CDDO-Me and carfilzomib, but only additive effects between CDDO-Me and bortezomib. These experiments were performed in MM.1S cells and confirmed with adjusted concentrations in MOLP-8 cells. * p < 0.05 by unpaired Student’s two-tailed t-test. The individual data points indicate averages and the error bars standard deviations; (C) Model of proposed drug effects on the proteasome and on LonP1.