Adipocyte maturation impacts daunorubicin disposition and metabolism

IF 4.4 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

European Journal of Clinical Investigation Pub Date : 2024-09-10 DOI:10.1111/eci.14307

Zeyang Li, Rachael Ngu, Aditya Anil Naik, Kaitlyn Trinh, Vladislava Paharkova, Hanyue Liao, Yulu Liu, Cindy Zhuang, Danh Le, Hua Pei, Isaac Asante, Steven D. Mittelman, Stan Louie

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引用次数: 0

Abstract

IntroductionAcute 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.ObjectivesThis study evaluated the effect of adipocyte maturation on sequestration and metabolism of chemotherapeutic drug daunorubicin (DNR).MethodsUsing 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.ResultsThis 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.ConclusionFat 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.

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脂肪细胞的成熟会影响多柔比星的处置和代谢

导言急性淋巴细胞白血病（ALL）是儿童白血病中最常见的一种，可进行有效的化疗。然而，肥胖与急性淋巴细胞白血病较高的化疗耐药率和较低的无事件生存率有关。本研究评估了脂肪细胞成熟对化疗药物达乌鲁比星（DNR）螯合和代谢的影响。方法采用靶向液相色谱-质谱/质谱多分析物检测法，研究了人前脂肪细胞和脂肪细胞系中 DNR 的螯合和代谢情况，同时还评估了 DNR 代谢酶醛酮还原酶（AKR）和羰基还原酶（CBR）的表达情况。此外，为了确定最能代谢 DNR 的 AKR/CBR 同工酶，对重组人 AKR 和 CBR 酶进行了 DNR 代谢。结果本报告显示，脂肪细胞的成熟会上调 AKR 和 CBR 酶的表达（4 至 60 倍，p < .05），与前脂肪细胞相比，这与脂肪细胞中 DNR 的螯合和代谢增强（约 30%，p < .05）呈正相关。结论脂肪是一种可扩张的组织，当受到肥胖刺激时，它可以封存和解毒 DNR，这可能是通过上调 DNR 代谢酶 AKR1C3 和 CBR1 实现的。我们的数据部分解释了为什么肥胖的 ALL 患者更有可能对 DNR 产生化疗耐药性，并为针对肥胖降低 DNR 化疗耐药性的潜在临床研究提供了证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Clinical Investigation 医学-医学：内科

CiteScore

9.50

自引率

3.60%

发文量

192

审稿时长

1 months

期刊介绍： EJCI considers any original contribution from the most sophisticated basic molecular sciences to applied clinical and translational research and evidence-based medicine across a broad range of subspecialties. The EJCI publishes reports of high-quality research that pertain to the genetic, molecular, cellular, or physiological basis of human biology and disease, as well as research that addresses prevalence, diagnosis, course, treatment, and prevention of disease. We are primarily interested in studies directly pertinent to humans, but submission of robust in vitro and animal work is also encouraged. Interdisciplinary work and research using innovative methods and combinations of laboratory, clinical, and epidemiological methodologies and techniques is of great interest to the journal. Several categories of manuscripts (for detailed description see below) are considered: editorials, original articles (also including randomized clinical trials, systematic reviews and meta-analyses), reviews (narrative reviews), opinion articles (including debates, perspectives and commentaries); and letters to the Editor.