Lovastatin induces a pronounced differentiation response in acute myeloid leukemias

We recently identified HMG-CoA reductase, the rate-limiting enzyme of the m evalonate pathway, as a potential therapeutic target of various retinoic ac id responsive cancers. Lovastatin, a competitive inhibitor of HMG-CoA reduc tase, induced a retinoic acid-like differentiation response followed by ext ensive apoptosis in neuroblastoma cell lines at relatively low concentratio ns (<20<mu>M) of this agent. More recently, we demonstrated that acute myel oid leukemias but not acute lymphocytic leukemias also displayed increased sensitivity to lovastatin-induced apoptosis. In this study, we examined the ability of lovastatin to induce differentiation of acute myeloid leukemic cells and to evaluate the role differentiation may hold in the anti-leukemi c properties of this agent, Increased expression of the leukocyte integrins CD 11b and CD18 as well as down-regulation of the anti-apoptotic gene bcl- 2 are associated with late stage differentiation of the myeloid lineage and retinoic acid induced maturation of acute myeloid leukemic cells. Lovastat in exposure induced increased expression of CD11b and CD18 markers similar to retinoic acid treatment. Following 24hrs exposure to 20 muM lovastatin, all 7 acute myeloid leukemia cell lines rested showed a decrease in bcl-2 m RNA expression while only 1/5 acute lymphocytic leukemia cell lines showed a similar response. A role for bcl-2 in the apoptotic response of acute mye loid leukemia cells to lovastatin was demonstrated as exogenous constitutiv e expression of bcl-2 in the AML-5 cell line inhibited apoptosis in a time and dose dependent manner. Thus, lovastatin exposure of acute myeloid leuke mia cells induced a differentiation response that may contribute to the the rapeutic potential of this agent in the treatment of this disease.