Lovastatin alters the isoprenoid biosynthetic pathway in acute myelogenous leukemia cells in vivo.
Lovastatin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase (HMGR), is used therapeutically to lower plasma cholesterol levels and has garnered attention for its cytotoxic effects in leukemia cells. In this study, escalating doses of lovastatin were administered to nine patients with acute myelogenous leukemia. Peripheral blood leukemia cells were drawn pre- and post-lovastatin dosing. Plasma lovastatin bioactivity ranged up to 234 nM lovastatin equivalents. Our results show that in vivo lovastatin, at up to 200 mg/dose, induces an increased activity of leukemia cell HMGR and alters leukemia cell proliferation without discernibly altering Ras processing.
Lewis
Kriste A
KA
Department of Internal Medicine, College of Medicine, University of Iowa, C32-I GH, 200 Hawkins Drive, Iowa City, IA 52242-1081, USA.
Holstein
Sarah A
SA
Hohl
Raymond J
RJ
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008148:Lovastatin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D017368:Protein Prenylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D013729:Terpenes / Q000378:metabolism*
D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013729:Terpenes; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)