Statins interact synergistically with UCN-01 to induce apoptosis in human malignant hematopoietic cells. (A) Human myelomonoyctic leukemia U937 cells were exposed for 18 hours to 100 nM UCN-01 (UCN) with or without 20 μM lovastatin (LV), 40 μM fluvastatin (FV), or 30 μM simvastatin (SV), respectively, after which the percentage of annexin V⁺ cells exhibiting either annexin V⁺/PI⁻ (early apoptosis) or annexin V⁺/PI⁺ (late apoptosis) was determined by annexin V–FITC/PI staining and flow cytometry as described in “Analysis of apoptosis and clonogenicity.” (B) Human myeloma U266 cells were exposed for 48 hours to 150 nM UCN-01 with or without 10 μM lovastatin, 20 μM fluvastatin (FV), or 10 μM simvastatin (SV), respectively, after which the percentage of apoptotic cells was determined as described in panel A. For panels A and B, results represent the means ± SD for 3 separate experiments performed in triplicate. (C-D) U937 and U266 cells were exposed to a range of lovastatin (5 to 25 μM) and UCN-01 (50 to 250 nM) concentrations alone and in combination at a fixed ratio (eg, U937, 1:0.005; U266, 1:0.01) for 18 hours (U937) or 48 hours (U266). At the end of the exposure intervals, the percentage of annexin V⁺ cells was determined for each condition; fractional effect values were determined by comparing results with those of untreated controls, and median dose effect analysis was employed to characterize the nature of the interaction between lovastatin and UCN-01. CI values less than 1.0 (horizontal line) denote a synergistic interaction. The results of representative experiments are shown; 2 additional studies yielded equivalent results.