Adipocyte maturation impacts daunorubicin disposition and metabolism.

Autor: Li Z; Alfred Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA., Ngu R; Alfred Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA., Naik AA; Alfred Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA., Trinh K; Alfred Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA., Paharkova V; Division of Pediatric Endocrinology, University of California Los Angeles (UCLA) Children's Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, California, USA., Liao H; College of Pharmacy, University of Houston, Houston, Texas, USA., Liu Y; Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan., Zhuang C; Norton College of Medicine, SUNY Upstate Medical University, Syracuse, New York, USA., Le D; Viterbi School of Engineering, University of Southern California, Los Angeles, California, USA., Pei H; Alfred Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA., Asante I; Alfred Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA.; Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA., Mittelman SD; Division of Pediatric Endocrinology, University of California Los Angeles (UCLA) Children's Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, California, USA., Louie S; Alfred Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA.; Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Jazyk: angličtina
Zdroj: European journal of clinical investigation [Eur J Clin Invest] 2024 Dec; Vol. 54 (12), pp. e14307. Date of Electronic Publication: 2024 Sep 10.
DOI: 10.1111/eci.14307
Abstrakt: Introduction: 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.
Objectives: This study evaluated the effect of adipocyte maturation on sequestration and metabolism of chemotherapeutic drug daunorubicin (DNR).
Methods: 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.
Results: 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.
Conclusion: 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.
(© 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.)
Databáze: MEDLINE
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