Classic and targeted anti‐leukaemic agents interfere with the cholesterol biogenesis metagene in acute myeloid leukaemia: Therapeutic implications

Autor: Fangli Chen, Xue Wu, H. Scott Boswell, Cristina Mariana Niculite, Daniela N. Petrusca, George A. Calin, Bin Guo, Adriana L. Rogozea, Heiko Konig, Marilena Gilca, Shawn Griffin, Susan Rice
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Intracellular Space
Apoptosis
Disease
Drug resistance
Translational Research
Biomedical
0302 clinical medicine
Rosuvastatin Calcium
Aged
80 and over
Gene Expression Regulation
Leukemic
Cytarabine
Middle Aged
Leukemia
Myeloid
Acute
medicine.anatomical_structure
030220 oncology & carcinogenesis
Molecular Medicine
Original Article
Female
medicine.drug
Adult
Statin
medicine.drug_class
Down-Regulation
statins
Young Adult
03 medical and health sciences
Cell Line
Tumor
Lipid biosynthesis
medicine
Humans
acute myeloid leukaemia
Rosuvastatin
Benzothiazoles
Aged
Cell Proliferation
hypoxia
business.industry
Phenylurea Compounds
cholesterol
Original Articles
Cell Biology
In vitro
Biosynthetic Pathways
030104 developmental biology
Cancer research
Bone marrow
Hydroxymethylglutaryl-CoA Reductase Inhibitors
business
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-4934
1582-1838
DOI: 10.1111/jcmm.15339
Popis: Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O2 compartments, such as bone marrow (BM) niches, are well‐recognized hosts of drug‐resistant leukaemic cells, standard in vitro studies are routinely performed under supra‐physiologic (21% O2, ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy‐induced vulnerability in AML cells under low O2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high‐potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher‐potency statin (eg rosuvastatin)–based combination therapies to enhance targeting residual AML cells that reside in low O2 environments.
Databáze: OpenAIRE
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