Biology subjects

Pantel, A.

Publications and source records attributed to Pantel, A..

3 recordsLinked to original sources

bioRxiv2026

L-5--glutamine PET of Breast Cancer: Kinetic Analysis in Mouse Models to Evaluate Glutamine Metabolism

BackgroundGlutamine addiction is a hallmark of aggressive tumors, yet glutaminase (GLS1) inhibitor CB-839 showed disappointing anti-tumor efficacy in clinical trials. L-5-[{superscript 1}{superscript 1}C]-glutamine ([{superscript 1}{superscript 1}C]glutamine) PET enables non-invasive assessment of glutamine metabolism in vivo, providing a tool to test mechanistic hypotheses, and identify tumors likely to respond to GLS1 inhibition: focusing on compartmentation of GLS1-derived glutamate, CB-839 impact on flux, and reciprocal glutamine synthesis. MethodsGlutaminolytic TNBC (HCC1806) and poorly glutaminolytic ER+ (MCF-7) xenograft mice with or without CB-839, underwent dynamic [11C]glutamine PET. HPLC quantified fractional radioactivity of [11C]glutamine, soluble metabolites ([11C]glutamate, [11C]CO2), and macromolecule-incorporated metabolites from blood and tumor. A four-tissue compartment model characterized GLS1 activity (kGLS) and flux, glutamine synthetase activity (kGS), and subcellular glutamate distribution by comparing single vs. dual glutamate pool models. Averaged tumor curves and HPLC-derived tumor metabolites were fit. Monte Carlo simulations assessed parameter estimation performance. ResultsThe single glutamate pool model showed high correlations between kGLS and other parameters, yielding inflated kGLS estimates. The dual glutamate pool model reduced correlations, improved kGLS recovery, and yielded subcellular glutamate distributions consistent with in vitro measurements. In TNBC, kGLS was 3-fold higher than ER+ tumors (non-overlapping 95% CI) with glutamate concentrated in the mitochondrial compartment. CB-839 reduced kGLS in TNBC and depleted mitochondrial glutamate (non-overlapping 95% CI), though glutaminolytic flux showed no distinguishable change. ER+ tumors showed higher kGS compared to TNBC. Conclusion[11C]glutamine PET kinetic analysis reveals distinct glutamine metabolic phenotypes in breast cancer subtypes. Preserved glutaminolytic flux and cytosolic glutamate in TNBC provide mechanistic hypotheses for clinical failure of GLS1 inhibitors, informing ongoing studies.

bioengineering↗

bioRxiv2023

Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutamate export and glutaminase

In triple-negative breast cancer (TNBC) that relies on catabolism of amino acid glutamine, glutaminase (GLS) converts glutamine to glutamate, which facilitates glutathione synthesis by mediating the enrichment of intracellular cystine via xCT antiporter activity. To overcome chemo resistant TNBC, we have tested a strategy of disrupting cellular redox balance by inhibition of GLS and xCT by CB839 and Erastin, respectively. Key findings of our study include: 1. Dual metabolic inhibition (CB839+Erastin) led to significant increases of cellular superoxide level in both parent and chemo resistant TNBC cells, but superoxide level was distinctly lower in resistant cells. 2. Dual metabolic inhibition combined with doxorubicin or cisplatin induced significant apoptosis in TNBC cells and is associated with high degrees of GSH depletion. In vivo, dual metabolic inhibition plus cisplatin led to significant growth delay of chemo resistant human TNBC xenografts. 3. Ferroptosis is induced by doxorubicin (DOX) but not by cisplatin or paclitaxel. Addition of dual metabolic inhibition to DOX chemotherapy significantly enhanced ferroptotic cell death. 4. Significant changes in cellular metabolites concentration preceded transcriptome changes revealed by single cell RNA sequencing, underscoring the potential of capturing early changes in metabolites as pharmacodynamic markers of metabolic inhibitors. Here we demonstrated that 4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) PET detected xCT blockade by Erastin or its analog in mice bearing human TNBC xenografts. In summary, our study provides compelling evidence for the therapeutic benefit and feasibility of non-invasive monitoring of dual metabolic blockade as a translational strategy to sensitize chemo resistant TNBC to cytotoxic chemotherapy.

cancer biology↗

bioRxiv2021

Investigating pathogenicity and virulence of Staphylococcus pettenkoferi: an emerging pathogen

Staphylococcus pettenkoferi is a coagulase-negative Staphylococcus identified in 2002 that has been implicated in human diseases as an opportunistic pathogenic bacterium. Its multiresistant character is becoming a major health problem, yet the pathogenicity of S. pettenkoferi is poorly characterized. In this study, pathogenicity of a S. pettenkoferi clinical isolate from diabetic foot osteomyelitis was compared to a Staphylococcus aureus strain in various in vitro and in vivo experiments. Growth kinetics were compared against S. aureus and bacteria survival was assessed in the RAW 264.7 murine macrophage cell line, the THP-1 human leukemia monocytic cell line and the HaCaT human keratinocyte cell line. Ex vivo analysis were performed in whole blood survival assays, and in vivo assays via the infection model of zebrafish embryos. Moreover, whole-genome analysis was performed. Our results showed that S. pettenkoferi was able to survive in human blood, human keratinocytes, murine macrophages, and human macrophages. S. pettenkoferi demonstrated its virulence by causing substantial embryo mortality in the zebrafish model. Genomic analysis revealed virulence factors such as biofilm- (e.g., icaABCD; rsbUVW) and regulator- (e.g., agr, mgrA, sarA, saeS) encoding genes well characterized in S. aureus. This study thus advances the knowledge of this under investigated pathogen and validates the zebrafish infection model for this bacterium.

microbiology↗