{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360292619624671232.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1182/blood-2002-07-2283"}},{"identifier":{"@type":"URI","@value":"http://ashpublications.org/blood/article-pdf/101/9/3628/1257066/h80903003628.pdf"}}],"dc:title":[{"@value":"Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:p>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.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380292619624671235","@type":"Researcher","foaf:name":[{"@value":"Henry Y. Li"}],"jpcoar:affiliationName":[{"@value":"From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; the Department of Medicine, University of Washington, Seattle; and the Department of Pathology, University of New Mexico and UNM Cancer Center, Albuquerque."}]},{"@id":"https://cir.nii.ac.jp/crid/1380292619624671234","@type":"Researcher","foaf:name":[{"@value":"Frederick R. Appelbaum"}],"jpcoar:affiliationName":[{"@value":"From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; the Department of Medicine, University of Washington, Seattle; and the Department of Pathology, University of New Mexico and UNM Cancer Center, Albuquerque."}]},{"@id":"https://cir.nii.ac.jp/crid/1380292619624671236","@type":"Researcher","foaf:name":[{"@value":"Cheryl L. Willman"}],"jpcoar:affiliationName":[{"@value":"From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; the Department of Medicine, University of Washington, Seattle; and the Department of Pathology, University of New Mexico and UNM Cancer Center, Albuquerque."}]},{"@id":"https://cir.nii.ac.jp/crid/1380292619624671233","@type":"Researcher","foaf:name":[{"@value":"Richard A. Zager"}],"jpcoar:affiliationName":[{"@value":"From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; the Department of Medicine, University of Washington, Seattle; and the Department of Pathology, University of New Mexico and UNM Cancer Center, Albuquerque."}]},{"@id":"https://cir.nii.ac.jp/crid/1380292619624671232","@type":"Researcher","foaf:name":[{"@value":"Deborah E. Banker"}],"jpcoar:affiliationName":[{"@value":"From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; the Department of Medicine, University of Washington, Seattle; and the Department of Pathology, University of New Mexico and UNM Cancer Center, Albuquerque."}]}],"publication":{"publicationIdentifier":[{"@type":"EISSN","@value":"15280020"},{"@type":"PISSN","@value":"00064971"},{"@type":"PISSN","@value":"https://id.crossref.org/issn/00064971"}],"prism:publicationName":[{"@value":"Blood"}],"dc:publisher":[{"@value":"American Society of Hematology"}],"prism:publicationDate":"2003-05-01","prism:volume":"101","prism:number":"9","prism:startingPage":"3628","prism:endingPage":"3634"},"reviewed":"false","url":[{"@id":"http://ashpublications.org/blood/article-pdf/101/9/3628/1257066/h80903003628.pdf"}],"createdAt":"2003-04-21","modifiedAt":"2021-06-06","relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360283691833823104","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Five-aza-2′-deoxycytidine-induced hypomethylation of cholesterol 25-hydroxylase gene is responsible for cell death of myelodysplasia/leukemia cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1360846644394649984","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"2-Hydroxypropyl-β-Cyclodextrin Acts as a Novel Anticancer Agent"}]},{"@id":"https://cir.nii.ac.jp/crid/1390001205217833600","@type":"Article","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@language":"en","@value":"Transcriptional Response of Wild-Type and Ataxia Telangiectasia Lymphoblasts Following Exposure to Equitoxic doses of Ionizing Radiation"}]},{"@id":"https://cir.nii.ac.jp/crid/1390282763010141440","@type":"Article","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@language":"ja","@value":"Pravastatin投与による白血球数の減少は冠動脈プラーク退縮の予測因子である : 新たなるプラーク退縮, 安定化マーカーの探究(1. 急性冠症候群の診断・治療の最前線, <特集>第69回日本循環器学会学術集会)"}]}],"dataSourceIdentifier":[{"@type":"CROSSREF","@value":"10.1182/blood-2002-07-2283"},{"@type":"CROSSREF","@value":"10.1038/srep16709_references_DOI_WK3vfRzhlrRKOV6wttdQovIcRbY"},{"@type":"CROSSREF","@value":"10.1269/jrr.0594_references_DOI_WK3vfRzhlrRKOV6wttdQovIcRbY"},{"@type":"CROSSREF","@value":"10.1253/jjcsc.13.2_213_references_DOI_WK3vfRzhlrRKOV6wttdQovIcRbY"},{"@type":"CROSSREF","@value":"10.1371/journal.pone.0141946_references_DOI_WK3vfRzhlrRKOV6wttdQovIcRbY"}]}