Lovastatin induces a pronounced differentiation response in acute myeloid leukemias.
We recently identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, as a potential therapeutic target of various retinoic acid responsive cancers. Lovastatin, a competitive inhibitor of HMG-CoA reductase, induced a retinoic acid-like differentiation response followed by extensive apoptosis in neuroblastoma cell lines at relatively low concentrations (<20 microM) of this agent. More recently, we demonstrated that acute myeloid 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-leukemic properties of this agent. Increased expression of the leukocyte integrins CD11b 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. Lovastatin exposure induced increased expression of CD11b and CD18 markers similar to retinoic acid treatment. Following 24 hrs exposure to 20 microM lovastatin, all 7 acute myeloid leukemia cell lines tested showed a decrease in bcl-2 mRNA 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 myeloid leukemia cells to lovastatin was demonstrated as exogenous constitutive 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 leukemia cells induced a differentiation response that may contribute to the therapeutic potential of this agent in the treatment of this disease.
Dimitroulakos
J
J
Department of Cellular and Molecular Biology, Ontario Cancer Institute, University Health Network, Toronto, Canada.
Thai
S
S
Wasfy
G H
GH
Hedley
D W
DW
Minden
M D
MD
Penn
L Z
LZ
D000208:Acute Disease; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018821:CD18 Antigens / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002648:Child; D015536:Down-Regulation / Q000187:drug effects; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D008148:Lovastatin / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D008148:Lovastatin