Co-administration of simvastatin and cytotoxic drugs is advantageous in myeloma cell lines

We have evaluated the potential application of simvastatin (Sim) combined with conventional cytotoxic drugs for the treatment of multiple myeloma. RPMI 8226 and U266 myeloma cells seeded in culture plates were treated with Sim (5 and 10 muM, respectively) combined with melphalan (Mel; 25 and 20 muM, respectively) or dexamethasone (Dex; 1 muM). We assessed cell cycle (propidium iodide staining and flow cytometric analysis), cell morphology, viability (WST1), total cell count and cell death (Trypan blue exclusion). Sim significantly enhanced the anti-myeloma activity of cytotoxic agents in vitro (p<0.05). Incubation of U266 and RPMI 8226 with Sim prior to Mel increased the cytotoxicity in an additive manner, whereas the exposure of U266 to combined Sim and Dex resulted in a synergistic amplification of the individual effects. Combined application of Dex and Sim to RPMI 8226 cells resulted in antagonistic activity. The possible roles of Ras and phosphoinositol 3-kinase are discussed. (C) 2004 Lippincott Williams Wilkins.