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      Emerging Metabolic Targets in the Therapy of Hematological Malignancies

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      BioMed Research International
      Hindawi Publishing Corporation

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          Abstract

          During the last decade, the development of anticancer therapies has focused on targeting neoplastic-related metabolism. Cancer cells display a variety of changes in their metabolism, which enable them to satisfy the high bioenergetic and biosynthetic demands for rapid cell division. One of the crucial alterations is referred to as the “Warburg effect”, which involves a metabolic shift from oxidative phosphorylation towards the less efficient glycolysis, independent of the presence of oxygen. Although there are many examples of solid tumors having altered metabolism with high rates of glucose uptake and glycolysis, it was only recently reported that this phenomenon occurs in hematological malignancies. This review presents evidence that targeting the glycolytic pathway at different levels in hematological malignancies can inhibit cancer cell proliferation by restoring normal metabolic conditions. However, to achieve cancer regression, high concentrations of glycolytic inhibitors are used due to limited solubility and biodistribution, which may result in toxicity. Besides using these inhibitors as monotherapies, combinatorial approaches using standard chemotherapeutic agents could display enhanced efficacy at eradicating malignant cells. The identification of the metabolic enzymes critical for hematological cancer cell proliferation and survival appears to be an interesting new approach for the targeted therapy of hematological malignancies.

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          On the origin of cancer cells.

          O WARBURG (1956)
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            Cancer's molecular sweet tooth and the Warburg effect.

            More than 80 years ago, the renowned biochemist Otto Warburg described how cancer cells avidly consume glucose and produce lactic acid under aerobic conditions. Recent studies arguing that cancer cells benefit from this phenomenon, termed the Warburg effect, have renewed discussions about its exact role as cause, correlate, or facilitator of cancer. Molecular advances in this area may reveal tactics to exploit the cancer cell's "sweet tooth" for cancer therapy.
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              Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function.

              The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase. However, the Glc-6-P produced can then enter one or more of several alternative pathways. Selective expression of isozymic forms of hexokinase, differing in catalytic and regulatory properties as well as subcellular localization, is likely to be an important factor in determining the pattern of Glc metabolism in mammalian tissues/cells. Despite their overall structural similarity, the Type I, Type II and Type III isozymes differ in important respects. All three isozymes are inhibited by the product, Glc-6-P, but with the Type I isozyme, this inhibition is antagonized by P(I), whereas with the Type II and Type III isozymes, P(i) actually causes additional inhibition. Reciprocal changes in intracellular levels of Glc-6-P and P(i) are closely associated with cellular energy status, and it is proposed that the response of the Type I isozyme to these effectors adapts it for catabolic function, introducing Glc into glycolytic metabolism for energy production. In contrast, the Type II, and probably the Type III, isozymes are suggested to serve primarily anabolic functions, e.g. to provide Glc-6-P for glycogen synthesis or metabolism via the pentose phosphate pathway for lipid synthesis. Type I hexokinase binds to mitochondria through interaction with porin, the protein that forms channels through which metabolites traverse the outer mitochondrial membrane. Several experimental approaches have led to the conclusion that the Type I isozyme, bound to actively phosphorylating mitochondria, selectively uses intramitochondrial ATP as substrate. Such interactions are thought to facilitate coordination of the introduction of Glc into glycolysis, via the hexokinase reaction, with the terminal oxidative stages of Glc metabolism occurring in the mitochondria, thus ensuring an overall rate of Glc metabolism commensurate with cellular energy demands and avoiding excessive production of lactate. The Type II isozyme also binds to mitochondria. Whether such coupling occurs with mitochondrially bound Type II hexokinase in normal tissues, and how it might be related to the proposed anabolic role of this isozyme, remain to be determined. The Type III isozyme lacks the hydrophobic N-terminal sequence known to be critical for binding of the Type I and Type II isozymes to mitochondria. Immunolocalization studies have indicated that, in many cell types, the Type III has a perinuclear localization, the possible metabolic consequences of which remain unclear.
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                Author and article information

                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi Publishing Corporation
                2314-6133
                2314-6141
                2013
                18 August 2013
                : 2013
                : 946206
                Affiliations
                University of Bern, Department of Clinical Research, Division of Pediatric Hematology/Oncology, Murtenstrasse 31, 3010 Bern, Switzerland
                Author notes

                Academic Editor: Beric Henderson

                Author information
                http://orcid.org/0000-0003-4882-3527
                http://orcid.org/0000-0001-9107-2947
                Article
                10.1155/2013/946206
                3759275
                24024216
                dd5475c6-56ff-4598-8178-2a87e1be7bbb
                Copyright © 2013 Zaira Leni et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 April 2013
                : 15 July 2013
                : 15 July 2013
                Funding
                Funded by: http://dx.doi.org/10.13039/501100001711 Swiss National Science Foundation
                Award ID: 31003A-120294
                Funded by: http://dx.doi.org/10.13039/501100001711 Swiss National Science Foundation
                Award ID: 31003A-146464
                Categories
                Review Article

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