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      Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302

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          Abstract

          Background

          Hypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, to date, have begun to show clinical efficacy. However, clinical HAPs activity could be improved. In this study, we sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models.

          Results

          Three human PDAC cell lines with varying sensitivity to TH-302 (Hs766t > MiaPaCa-2 > SU.86.86) were used to establish PDAC xenograft models. PDAC cells were metabolically profiled in vitro and in vivo using the Seahorse XF system and hyperpolarized 13C pyruvate MRI, respectively, in addition to quantitative immunohistochemistry. The effect of exogenous pyruvate on tumor oxygenation was determined using electroparamagnetic resonance (EPR) oxygen imaging. Hs766t and MiaPaCa-2 cells exhibited a glycolytic phenotype in comparison to TH-302 resistant line SU.86.86. Supporting this observation is a higher lactate/pyruvate ratio in Hs766t and MiaPaCa xenografts as observed during hyperpolarized pyruvate MRI studies in vivo. Coincidentally, response to exogenous pyruvate both in vitro (Seahorse oxygen consumption) and in vivo (EPR oxygen imaging) was greatest in Hs766t and MiaPaCa models, possibly due to a higher mitochondrial reserve capacity. Changes in oxygen consumption and in vivo hypoxic status to pyruvate were limited in the SU.86.86 model. Combination therapy of pyruvate plus TH-302 in vivo significantly decreased tumor growth and increased survival in the MiaPaCa model and improved survival in Hs766t tumors.

          Conclusions

          Using metabolic profiling, functional imaging, and computational modeling, we show improved TH-302 activity by transiently increasing tumor hypoxia metabolically with exogenous pyruvate. Additionally, this work identified a set of biomarkers that may be used clinically to predict which tumors will be most responsive to pyruvate + TH-302 combination therapy. The results of this study support the concept that acute increases in tumor hypoxia can be beneficial for improving the clinical efficacy of HAPs and can positively impact the future treatment of PDAC and other cancers.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s40170-014-0026-z) contains supplementary material, which is available to authorized users.

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          Most cited references28

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          Hypoxia-inducible expression of tumor-associated carbonic anhydrases.

          The transcriptional complex hypoxia-inducible factor-1 (HIF-1) has emerged as an important mediator of gene expression patterns in tumors, although the range of responding genes is still incompletely defined. Here we show that the tumor-associated carbonic anhydrases (CAs) are tightly regulated by this system. Both CA9 and CA12 were strongly induced by hypoxia in a range of tumor cell lines. In renal carcinoma cells that are defective for the von Hippel-Lindau (VHL) tumor suppressor, up-regulation of these CAs is associated with loss of regulation by hypoxia, consistent with the critical function of pVHL in the regulation of HIF-1. Further studies of CA9 defined a HIF-1-dependent hypoxia response element in the minimal promoter and demonstrated that tight regulation by the HIF/pVHL system was reflected in the pattern of CA IX expression within tumors. Generalized up-regulation of CA IX in VHL-associated renal cell carcinoma contrasted with focal perinecrotic expression in a variety of non-VHL-associated tumors. In comparison with vascular endothelial growth factor mRNA, expression of CA IX demonstrated a similar, although more tightly circumscribed, pattern of expression around regions of necrosis and showed substantial although incomplete overlap with activation of the hypoxia marker pimonidazole. These studies define a new class of HIF-1-responsive gene, the activation of which has implications for the understanding of hypoxic tumor metabolism and which may provide endogenous markers for tumor hypoxia.
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            The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond.

            The monocarboxylate cotransporter (MCT) family now comprises 14 members, of which only the first four (MCT1-MCT4) have been demonstrated experimentally to catalyse the proton-linked transport of metabolically important monocarboxylates such as lactate, pyruvate and ketone bodies. SLC16A10 (T-type amino-acid transporter-1, TAT1) is an aromatic amino acid transporter whilst the other members await characterization. MCTs have 12 transmembrane domains (TMDs) with intracellular N- and C-termini and a large intracellular loop between TMDs 6 and 7. MCT1 and MCT4 require a monotopic ancillary protein, CD147, for expression of functional protein at the plasma membrane. Lactic acid transport across the plasma membrane is fundamental for the metabolism of and pH regulation of all cells, removing lactic acid produced by glycolysis and allowing uptake by those cells utilizing it for gluconeogenesis (liver and kidney) or as a respiratory fuel (heart and red muscle). The properties of the different MCT isoforms and their tissue distribution and regulation reflect these roles.
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              Anticancer Targets in the Glycolytic Metabolism of Tumors: A Comprehensive Review

              Cancer is a metabolic disease and the solution of two metabolic equations: to produce energy with limited resources and to fulfill the biosynthetic needs of proliferating cells. Both equations are solved when glycolysis is uncoupled from oxidative phosphorylation in the tricarboxylic acid cycle, a process known as the glycolytic switch. This review addresses in a comprehensive manner the main molecular events accounting for high-rate glycolysis in cancer. It starts from modulation of the Pasteur Effect allowing short-term adaptation to hypoxia, highlights the key role exerted by the hypoxia-inducible transcription factor HIF-1 in long-term adaptation to hypoxia, and summarizes the current knowledge concerning the necessary involvement of aerobic glycolysis (the Warburg effect) in cancer cell proliferation. Based on the many observations positioning glycolysis as a central player in malignancy, the most advanced anticancer treatments targeting tumor glycolysis are briefly reviewed.
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                Author and article information

                Contributors
                Jonathan.Wojtkowiak@Moffitt.Org
                hhcornnell@gmail.com
                matsumos@mail.nih.gov
                keita.saito@nih.gov
                YOICHI.TAKAKUSAGI@NIH.GOV
                prasanta.dutta@moffitt.org
                munju.kim@moffitt.org
                xiaomeng.zhang@moffitt.org
                rleo@azcc.arizona.edu
                kate.bailey@moffitt.org
                Gary.martinez@moffitt.org
                Mark.lloyd@moffitt.org
                cweber@email.arizona.edu
                james.mitchell3@nih.gov
                rlynch@email.arizona.edu
                abaker@azcc.arizona.edu
                robert.gatenby@moffitt.org
                kasia.rejniak@moffitt.org
                chart@thresholdpharm.com
                cherukum@mail.nih.gov
                robert.gillies@moffitt.org
                Journal
                Cancer Metab
                Cancer Metab
                Cancer & Metabolism
                BioMed Central (London )
                2049-3002
                29 January 2015
                29 January 2015
                2015
                : 3
                : 1
                : 2
                Affiliations
                [ ]Department of Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA
                [ ]Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA
                [ ]Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA
                [ ]Analytic Microscopy Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA
                [ ]Arizona Cancer Center, College of Medicine, University of Arizona, Tucson, AZ 85724 USA
                [ ]Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ 85724 USA
                [ ]Hematology/Oncology Section, College of Medicine, University of Arizona, Tucson, AZ 85724 USA
                [ ]Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 USA
                [ ]Threshold Pharmaceutical, San Francisco, CA 94080 USA
                [ ]Department of Oncologic Sciences, University of South Florida, Tampa, FL 33612 USA
                Article
                26
                10.1186/s40170-014-0026-z
                4310189
                25635223
                50dc7d30-3093-40a3-9a1d-4daaf9e256b6
                © Wojtkowiak et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 21 August 2014
                : 24 November 2014
                Categories
                Research
                Custom metadata
                © The Author(s) 2015

                hypoxia,hypoxia-activated prodrugs,th-302,tumor microenvironment,metabolism,pancreatic cancer,functional imaging,computational modeling

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