fig3

Figure 3. Selectivity of simvastatin-potentiating effect for APis. Effect of non-toxic concentrations of simvastatin (2-2.5 µM) on the growth inhibitory activity of the APis CHR2863 and bestatin, HDAC inhibitor prodrug CHR2875, and daunorubicin in U937/WT, U937/CHR2863^R0.2 and U937/CHR2863^R5 cells. Simvastatin potentiation factor is defined as the ratio of IC₅₀ (50% growth inhibition) of cell culture without statins vs. IC₅₀ of cell cultures in the presence of statins. Cell growth inhibition was determined after 72 h of drug exposure. Results depicted are the mean of two separate experiments (for bestatin) and the mean ± SD of 3-4 separate experiments for CHR2863, CHR2875 and daunorubicin. IC50 values of U937/WT, U937/CHR2863R0.2 and U937/CHR2863R5 cells for CHR2863 are: 52 ± 16 nM, 713 ± 212 nM, and 14,047 ± 5,521 nM, respectively; for Bestatin: 158 ± 15 μM, 169 ± 32 μM, and 177 ± 14 μM, respectively; for CHR2875: 158 ± 9 nM, 86 ± 13 nM, and 147 ± 36 nM, respectively; and for daunorubicin: 16 ± 1 nM, 16 ± 2 nM, and 15 ± 3 nM, respectively. APis: aminopeptidase inhibitors; CHR2863: (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester.