Adipocyte maturation impacts daunorubicin disposition and metabolism.

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.

Loss of 15-Lipoxygenase in Retinodegenerative RCS Rats.

Retinitis pigmentosa (RP) is a retinal degenerative disease associated with a diversity of genetic mutations. In a natural progression study (NPS) evaluating the molecular changes in Royal College of Surgeons (RCS) rats using lipidomic profiling, RNA sequencing, and gene expression analyses, changes associated with retinal degeneration from p21 to p60 were evaluated, where reductions in retinal ALOX15 expression corresponded with disease progression. This important enzyme catalyzes the formation of specialized pro-resolving mediators (SPMs) such as lipoxins (LXs), resolvins (RvDs), and docosapentaenoic acid resolvins (DPA RvDs), where reduced ALOX15 corresponded with reduced SPMs. Retinal DPA RvD2 levels were found to correlate with retinal structural and functional decline. Retinal RNA sequencing comparing p21 with p60 showed an upregulation of microglial inflammatory pathways accompanied by impaired damage-associated molecular pattern (DAMP) clearance pathways. This analysis suggests that ALXR/FPR2 activation can ameliorate disease progression, which was supported by treatment with an LXA4 analog, NAP1051, which was able to promote the upregulation of ALOX12 and ALOX15. This study showed that retinal inflammation from activated microglia and dysregulation of lipid metabolism were central to the pathogenesis of retinal degeneration in RP, where ALXR/FPR2 activation was able to preserve retinal structure and function.