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Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1308-1318
Increased Sensitivity of Acute Myeloid Leukemias to
Lovastatin-Induced Apoptosis: A Potential Therapeutic Approach
Jim Dimitroulakos,
Dana Nohynek,
Karen L. Backway,
David W. Hedley,
Herman Yeger,
Melvin H. Freedman,
Mark D. Minden, and
Linda Z. Penn
From the Departments of Cellular and Molecular Biology and
Experimental Therapeutics, the Ontario Cancer Institute, Toronto,
Ontario, Canada; the Departments of Paediatric Laboratory Medicine and
Haematology, The Hospital for Sick Children, Toronto, Ontario, Canada;
and the Departments of Medical Biophysics and Laboratory Medicine and
Pathobiology, University of Toronto, Toronto, Ontario, Canada.
We recently demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase, the rate-limiting enzyme of de novo cholesterol
synthesis, was 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 was triggered at lower
concentrations and occurred more rapidly than had been previously
reported in other tumor-derived cell lines, including breast and
prostate carcinomas. Because of the increased sensitivity of
neuroblastoma cells to lovastatin-induced apoptosis, we examined the
effect of this agent on a variety of tumor cells, including leukemic
cell lines and primary patient samples. Based on a variety of
cytotoxicity and apoptosis assays, the 6 acute lymphocytic leukemia
cell lines tested displayed a weak apoptotic response to lovastatin. In
contrast, the majority of the acute myeloid leukemic cell lines (6/7)
and primary cell cultures (13/22) showed significant 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 inhibitors as a therapeutic approach in the treatment of
acute myeloid leukemia.
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