Adipocyte maturation impacts daunorubicin disposition and metabolism.
adipocyte
cell differentiation
drug metabolism
liquid chromatography
mass spectrometry
obesity
Journal
European journal of clinical investigation
ISSN: 1365-2362
Titre abrégé: Eur J Clin Invest
Pays: England
ID NLM: 0245331
Informations de publication
Date de publication:
10 Sep 2024
10 Sep 2024
Historique:
received:
20
06
2024
accepted:
12
08
2024
medline:
10
9
2024
pubmed:
10
9
2024
entrez:
10
9
2024
Statut:
aheadofprint
Résumé
Acute lymphoblastic leukaemia (ALL) is the most common type of childhood leukaemia with effective chemotherapeutic treatment. However, obesity has been associated with higher ALL chemoresistance rates and lower event-free survival rates. The molecular mechanism of how obesity promotes chemotherapy resistance is not well delineated. This study evaluated the effect of adipocyte maturation on sequestration and metabolism of chemotherapeutic drug daunorubicin (DNR). Using targeted LC-MS/MS multi-analyte assay, DNR sequestration and metabolism were studied in human preadipocyte and adipocyte cell lines, where expressions of DNR-metabolizing enzymes aldo-keto reductases (AKR) and carbonyl reductases (CBR) were also evaluated. In addition, to identify the most DNR-metabolizing AKR/CBR isoforms, recombinant human AKR and CBR enzymes were subject to DNR metabolism. The results were further validated by AKR-, CBR-specific inhibitors. This report shows that adipocyte maturation upregulates expressions of AKR and CBR enzymes (by 4- to 60- folds, p < .05), which is positively associated with enhanced sequestration and metabolism of DNR in adipocytes compared to preadipocytes (by ~30%, p < .05). In particular, adipocyte maturation upregulates AKR1C3 and CBR1, which are the predominate metabolic enzyme isoforms responsible for DNR biotransformation to its metabolites. Fat is an expandable tissue that can sequester and detoxify DNR when stimulated by obesity, likely through the upregulation of DNR-metabolizing enzymes AKR1C3 and CBR1. Our data partially explains why obese ALL patients may be more likely to become chemoresistant towards DNR, and provides evidence for potential clinical investigation targeting obesity to reduce DNR chemoresistance.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14307Subventions
Organisme : NCI NIH HHS
ID : R01 CA213129
Pays : United States
Informations de copyright
© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.
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