Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: A potential therapeutic approach

We recently demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co A) reductase, the rate-limiting enzyme of de novo cholesterol synthesis, wa s a potential mediator of the biological effects of retinoic acid on human neuroblastoma cells. The HMG-CoA reductase inhibitor, lovastatin, which is used extensively in the treatment of hypercholesterolemia, induced a potent apoptotic response in human neuroblastoma cells. This apoptotic response w as triggered at lower concentrations and occurred more rapidly than had bee n previously reported in other tumor-derived cell lines, including breast a nd prostate carcinomas. Because of the increased sensitivity of neuroblasto ma cells to lovastatin-induced apoptosis, we examined the effect of this ag ent on a variety of tumor cells, including leukemic cell lines and primary patient samples. Based on a variety of cytotoxicity and apoptosis assays, t he 6 acute lymphocytic leukemia cell lines tested displayed a weak apoptoti c response to lovastatin. In contrast, the majority of the acute myeloid le ukemic cell lines (6/7) and primary cell cultures (13/22) showed significan t sensitivity to lovastatin-induced apoptosis, similar to the neuroblastoma cell response. Of significance, in the acute myeloid leukemia, but not the acute lymphocytic leukemia cell lines, lovastatin-induced cytotoxicity was pronounced even at the physiological relevant concentrations of this agent . Therefore, our study suggests the evaluation of HMG-CoA reductase inhibit ors as a therapeutic approach in the treatment of acute myeloid leukemia. ( C) 1999 by The American Society of Hematology.