Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice

• Published in: British journal of haematology Vol. 102; no. 2; pp. 522 - 527
• Main Authors: Clutterbuck, Robyn D., Millar, Barbara C., Powles, Ray L., Newman, Ann, Catovsky, Daniel, Jarman, Michael, Millar, John L.
• Format: Journal Article
• Language: English
• Published: Oxford, U.K. & Cambridge, USA Blackwell Science Ltd 01-07-1998; Blackwell; Blackwell Publishing Ltd
• Subjects: Acute Disease; Animals; Antineoplastic agents; Biological and medical sciences; Cell Division - drug effects; Cell Survival - drug effects; Chemotherapy; Dose-Response Relationship, Drug; Female; Flow Cytometry; Hematology; HL-60 Cells; human leukaemia; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - pathology; Medical sciences; Mice; Mice, SCID; Neoplasm Transplantation; Pharmacology. Drug treatments; SCID mice; simvastatin; Simvastatin - therapeutic use; Antineoplastic agent; Human; Promyelocytic leukemia; Cell proliferation; Animal model; Acute; Simvastatin; Rodentia; Malignant hemopathy; HL60 cell line; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Established cell line; Inhibition; Acute myelocytic leukemia
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.1998.00783.x

SCID mice were inoculated intravenously with cells from the human HL60 myeloblastic leukaemia cell line and then treated with the 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, simvastatin, by subcutaneous continuous infusion. The effect of the drug was measured by subsequent colony formation of surviving HL60 cells in vitro and flow cytometry. The number of clonogenic HL60 cells was reduced in the bone marrow of mice that received simvastatin compared with control mice by 65% and 68% in two separate experiments. The number of clonogenic, normal, murine, bone marrow progenitor cells concomitantly exposed to simvastatin in vivo, was not affected in either experiment. Flow cytometric analysis of bone marrow and spleen cells confirmed these results by showing that simvastatin had reduced the percentage of human leukaemia cells in these tissues by 70% and 88% respectively.  The data show that the reported selective effect of simvastatin against acute myeloid leukaemia cells in vitro, can be extended to this in vivo model. HL60 bears an N‐ras mutation. In further in vitro studies, ketoconazole, an inhibitor of cholesterol biosynthesis post farnesyl pyrophosphate synthesis, had a similar effect to simvastatin on HL60 colony development. Furthermore, the clonogenicity of a population of N‐ras mutated, primary acute myeloid leukaemia (AML) cells was no more sensitive to simvastatin than a population without the mutation. The data suggest that the inhibition of AML cell proliferation by simvastatin may be independent of the RAS signalling pathway.