[1,2-13C2]-D-Glucose Profiles of the Serum, Liver, Pancreas, and DMBA-Induced Pancreatic Tumors of Rats

Boros, László G.; Lerner, Megan R.; Morgan, Daniel L.; Taylor, Stephanie L.; Bj, Smith; Postier, Russell G.; Brackett, Daniel J.

doi:10.1097/01.mpa.0000186524.53253.fb

Cited by 45 publications

(40 citation statements)

References 20 publications

(28 reference statements)

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“…However, [ 13 C 2 -1,2]Glc can distinguish the oxidative and nonoxidative branches of the PPP (Fig. 1) (23,24). R5P isotopologues containing more than one label reflect activity of both the oxidative and non-oxidative branches of PPP as additional 13 C label incorporation into R5P can only be derived through transaldolase and transketolase activity in the non-oxidative PPP branch (25).…”

Section: Pentose Phosphate Pathwaymentioning

confidence: 99%

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Bruntz

Lane

Higashi

et al. 2017

Journal of Biological Chemistry

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Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.Metabolism is the collection of predominantly enzyme-catalyzed biochemical transformations that meet the growth and survival demands of an organism. For nearly a century, scientists have documented profound metabolic changes that occur in tumors (1, 2). One of the earliest insights into cancer metabolism came when Otto Warburg noted increased uptake and fermentation of glucose (Glc) 3 to lactate in tumors relative to surrounding tissue, even in the presence of ample oxygen (2). Clinical cancer diagnosis exploits this "Warburg effect" by measuring uptake of the Glc analogue 18 F-deoxyglucose using positron emission tomography (PET), as the metabolic demands of differentiated, non-proliferating tissues generally require far less Glc than tumors (3).Oncoproteins and tumor suppressors are well-established regulators of metabolism, and mutations or dysregulated expression can lead to the altered metabolic phenotypes observed in many cancers (4, 5). Inactivating mutations in enzymes such as fumarate hydratase (FH) or succinate dehydrogenase (SDH) induce pathophysiological accumulation of substrates that inhibit other critical enzyme functions, whereas less common gain-of-function mutations such as in isocitrate dehydrogenases (IDH) produce metabolites that directly deregulate cellular processes (6). Additionally, cancer cells frequently express fetal isoforms of metabolic enzymes that are subject to different regulatory mechanisms to provide growth advantages (7). Gaining a systematic understanding of the metabolic changes that occur during carcinogenesis can thus be exploited for therapeutic and diagnostic purposes.Stable isotope-resolved metabolomics (SIRM) is a powerful approach developed by others and by us where isotopically enriched precursors such as [ 13 C 6 ]Glc are administered to a biological system, and the ensuing metabolic transformations are determined using appropriate analytic techniques to enable robust reconstruction of metabolic pathways (8 -11). Stable isotopes are non-radioactive and in SIRM practice are identical chemically and functionally to the most abundant isotope of that element. Incorporating stable isotopes such as 2 H, 13 C, or 15 N into biological precursors has long been used to trace their metabolism in living systems (12). SIRM is thus distinct from non-tracer-based metabolomics profiling for statistical models. Here, we review SIRM applications and demonstrate h...

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Section: Pentose Phosphate Pathwaymentioning

confidence: 99%

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Bruntz

Lane

Higashi

et al. 2017

Journal of Biological Chemistry

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“…Metabolism-The incorporation of 13 C atoms from a glucose tracer within RNA ribose can be used as an end point to evaluate the consequences of a metabolic perturbation such as tumor burden on host glucose homeostasis (29). Fig.…”

Section: Orthotopic Tumors Prepared From Shrna Control and Ampk␣1/2 Kmentioning

confidence: 99%

5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors

Laderoute

Calaoagan

Chao

et al. 2014

Journal of Biological Chemistry

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“…Early on, translational biomarkers of drug efficacy and safety were seen as a promising result of metabolomics research (Harrigan and Goodacre 2003;Colatsky and Sumner 2003;Mortishire-Smith et al 2004;Robertson 2005). One of the biggest areas of biomedical research for metabolomics has been in the area of cancer biomarkers (Boros et al 2005;Chung and Griffiths 2007;Lane et al 2008;Fan et al 2009;Spratlin et al 2009;Sreekumar et al 2009;Dong et al 2010;Nishiumi et al 2010;Sugimoto et al 2010). Metabolomics is also being used to discover biomarkers and biomarker patterns associated with drug effects (Watkins and German 2002;Morris and Watkins 2005;Maguire et al 2006;Morvan and Demidem 2007;KaddurahDaouk et al 2008), metabolic diseases (Yi et al 2008;Newgard et al 2009;Gall et al 2010;Oresic 2010), toxicity and organ-specific response to injury (Soga et al 2006;Waters et al 2006;Ebbels et al 2007;Beger et al 2008;Chen et al 2009;Boudonck et al 2009;Schnackenberg et al 2009;Aranibar et al 2010;Beger et al 2010;Robertson et al 2011), and interactions with gut microflora (Nicholson et al 2005;Robosky et al 2005;Martin et al 2008;Wikoff et al 2009).…”

Section: Introductionmentioning

confidence: 98%

Metabolomics data and the biomarker qualification process

Beger

Colatsky

2011

Metabolomics

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Since its initial applications in healthcare research over a decade ago, metabolomics has matured into a technology that can now reliably detect and quantify hundreds of metabolites in biofluids and tissue samples. With substantial improvements in analytical capabilities in recent years, metabolomics now has the potential to provide sensitive and specific biomarkers of health and disease status, drug toxicity and therapeutic efficacy. Although many of the clinical biomarkers currently in use are metabolites such as glucose, cholesterol, and creatinine, few, if any, new metabolites (or panel of metabolites) derived from metabolomic analyses have been submitted to the FDA as biomarker candidates. Under a recent FDA draft Guidance for Industry from the Center for Drug Evaluation and Research (CDER), biomarkers discovered using metabolomics, like those derived from genetic, transcriptomic, and proteomic studies, may be submitted to CDER for consideration as new drug development tools and entered into a formal biomarker qualification process. The qualification process begins with a letter of intent from the submitter, followed by discussions with FDA and then the submission of data supporting the performance of the biomarker within a specific context of use. CDER forms a Biomarker Qualification Review Team at the start of the interactive process to advise the biomarker developer on the type of information important to support the proposed context of use, and review the data that evaluates the biomarker for the proposed context of use when the biomarker development appears complete and the full supporting data are submitted. Once qualified, a biomarker can be used in drug development within the qualified context of use without requesting additional regulatory review concerning its suitability.

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[1,2-13C2]-D-Glucose Profiles of the Serum, Liver, Pancreas, and DMBA-Induced Pancreatic Tumors of Rats

Cited by 45 publications

References 20 publications

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

5′-AMP-activated Protein Kinase (AMPK) Supports the Growth of Aggressive Experimental Human Breast Cancer Tumors

Metabolomics data and the biomarker qualification process

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