title: Treatment with high-dose simvastatin inhibits geranylgeranylation in AML blast cells in a subset of AML patients.
abstract: It is currently unknown whether the in vitro effects observed with statins in acute myeloid leukemia (AML) cells, including lowering of cholesterol, inhibition of isoprenylation, and sensitization to chemotherapy, also occur in vivo. Therefore, AML mononuclear cells (MNCs) were isolated from 12 patients before and after 7 days of high-dose (7.5-15 mg/kg/day) simvastatin treatment. Parallel mouse studies were performed to have, in addition to AML cells, access to liver tissue, a major target of statins. Serum cholesterol levels were lowered by simvastatin in all patients, however, only limited changes in the messenger RNA expression of cholesterol metabolism genes were seen in patient and mouse MNCs compared to murine liver cells. Still, two out of seven patients displayed an increased in vitro chemosensitivity of their AML cells upon simvastatin treatment. Gene set enrichment analysis on microarray data of AML patient cells and Western blot analysis for the isoprenylated proteins DnaJ and Rap1 on murine and AML patient MNCs demonstrated that in vivo simvastatin treatment resulted in inhibition of geranylgeranylation in murine MNCs and in a subset of patient AML MNCs. In summary, our data demonstrate that simvastatin treatment results in chemosensitization and inhibition of geranylgeranylation in AML cells of a subset of patients.
authors: Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Karen
authors: K
authors: van der Weide
authors: Susan
authors: S
authors: de Jonge-Peeters
authors: Gerwin
authors: G
authors: Huls
authors: Rudolf S N
authors: RS
authors: Fehrmann
authors: Jan Jacob
authors: JJ
authors: Schuringa
authors: Folkert
authors: F
authors: Kuipers
authors: Elisabeth G E
authors: EG
authors: de Vries
authors: Edo
authors: E
authors: Vellenga
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D054876:Prenylation / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009363:Neoplasm Proteins; D002784:Cholesterol; D019821:Simvastatin