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. 2016 Jan 25;6:18953. doi: 10.1038/srep18953

Figure 7. Combination proteasome inhibition and HDAC inhibition induces increased caspase-9 activation and DNA fragmentation in vitro and cleavage of the caspase substrate, lamin A, in vivo.

Figure 7

(a) Caspase 9 in LN18 cells treated 16 h with 100 nM MRZ, 10 nM BTZ, 5 μM vorinostat, or combinations. (b,c) DNA fragmentation in LN18 cells treated with combinations of proteasome inhibitors and vorinostat (b) or panobinostat (c) for 48 h (*p < 0.05 compared to either single agent alone). (d) Combination index values for combinations of proteasome inhibitors and HDACi. Values <1 indicate synergy. Most highly synergistic doses are in bold font. (e) Treatment scheme for mice treated with combinations of proteasome inhibitors and vorinostat. Tumors developed for 14 days, followed by treatment for 2 weeks with IP injections of BTZ (1.0 mg/kg twice weekly), MRZ (0.15 mg/kg twice weekly), or VORI (50 mg/kg 5 times per week) before mice were sacrificed 24 h following the last treatment. (f) Representative images of IHC staining for cleaved lamin A in tumors of mice treated for 2 weeks with combinations of BTZ, MRZ, and VORI (40 × magnification). (g) The average number of cleaved lamin A-positive cells per field for individual mice treated as in (e,f). p-values indicate significant differences compared to the control group, 40× magnification. All error bars represent the standard error of the mean for N = 3 independent experiments.