title: Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses.
abstract: The mevalonate pathway produces many critical substances in cells, including sterols essential for membrane structure and isoprenoids vital to the function of many membrane proteins. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate pathway. Because cholesterol is a product of this pathway, HMG-CoA reductase inhibitors (statins) are used to treat hypercholesterolemia. Statins are also toxic to several malignancies, including acute myeloid leukemia (AML). Although this toxicity has been attributed to the inhibition of Ras/Rho isoprenylation, we have previously shown that statin toxicity in primary AML cells (AMLs) does not correlate with Ras isoprenylation or with activating Ras mutations. In other studies, we have shown that hypoxic and oxidant injuries induce cholesterol increments in renal tubule cells and that statins sensitize these cells to injury by blocking protective cholesterol responses. We now demonstrate that exposing particular AMLs to radiochemotherapy induces much greater cellular cholesterol increments than those seen in similarly treated normal bone marrow. Treatment of these AMLs with mevastatin or zaragozic acid (which inhibits cholesterol synthesis but not isoprenoid synthesis) attenuates the cholesterol increments and sensitizes cells to radiochemotherapy. The extent of toxicity is affected by the availability of extracellular lipoproteins, further suggesting that cellular cholesterol is critical to cell survival in particular AMLs. Because zaragozic acid does not inhibit isoprenoid synthesis, these data suggest that cholesterol modulation is an important mechanism whereby statins exert toxic effects on some AMLs and that cholesterol modulators may improve therapeutic ratios in AML by impacting cholesterol-dependent cytoresistance.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
authors.forename: Henry Y
authors.initials: HY
authors.lastname: Li
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Banker
mesh_terms: D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis* / Q000502:physiology; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004357:Drug Synergism; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008563:Membrane Lipids / Q000502:physiology; D017368:Protein Prenylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014233:Tricarboxylic Acids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D008563:Membrane Lipids; D011838:Radiation-Sensitizing Agents; D014233:Tricarboxylic Acids; D003561:Cytarabine; C075117:squalestatin 1; C012258:mevastatin; D002784:Cholesterol; D008148:Lovastatin; D003630:Daunorubicin