Synergy of cytosine arabinoside and lovastatin in human leukemia cells

The drug of choice for the treatment of leukemias has for many years been the antimetabolite agent cytosine arabinoside (ara-C). Lovastatin, an HMG-CoA reductase inhibitor is widely employed in the treatment of hypercholesterolemia. Recently there has been interest in its potential use as an adjunct to standard chemotherapeutic agents. In these studies we have examined the effects of lovastatin and ara-C in the human erythroleukemia K562 cell line and the ara-C resistant human T-lymphoblastic ARAC8D cell line. Lovastatin was found to have significant cytotoxic and antiproliferative effects in both cell lines. Furthermore, isobologram analysis demonstrated that there was a synergistic interaction between the two drugs in the K562 cell line. Lovastatin induced apoptosis in both cell lines as determined by DNA laddering and flow cytometric experiments. Western blot analysis demonstrated that ara-C neither altered RAS processing nor affected lovastatin's induced inhibition of RAS processing. Lovastatin was shown to inhibit MAPK activation both alone and in combination with ara-C. Although the nature of the interaction between lovastatin and ara-C is not fully understood, we have demonstrated that it does not occur at the level of RAS but may involve lovastatin's effect of downregulating MAPK activity and preventing ara-C-induced MAPK activation. These studies demonstrate a potentially beneficial interaction between lovastatin and ara-C that could be applied to the treatment of human leukemia.