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Efficacy of 2-halogen substituted d-glucose analogs in blocking glycolysis and killing “hypoxic tumor cells”

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Abstract

Purpose: Since 2-deoxy-D-glucose (2-DG) is currently in phase I clinical trials to selectively target slow-growing hypoxic tumor cells, 2-halogenated D-glucose analogs were synthesized for improved activity. Given the fact that 2-DG competes with D-glucose for binding to hexokinase, in silico modeling of molecular interactions between hexokinase I and these new analogs was used to determine whether binding energies correlate with biological effects, i.e. inhibition of glycolysis and subsequent toxicity in hypoxic tumor cells. Methods and Results: Using a QSAR-like approach along with a flexible docking strategy, it was determined that the binding affinities of the analogs to hexokinase I decrease as a function of increasing halogen size as follows: 2-fluoro-2-deoxy-D-glucose (2-FG) > 2-chloro-2-deoxy-D-glucose (2-CG) > 2-bromo-2-deoxy-D-glucose (2-BG). Furthermore, D-glucose was found to have the highest affinity followed by 2-FG and 2-DG, respectively. Similarly, flow cytometry and trypan blue exclusion assays showed that the efficacy of the halogenated analogs in preferentially inhibiting growth and killing hypoxic vs. aerobic cells increases as a function of their relative binding affinities. These results correlate with the inhibition of glycolysis as measured by lactate inhibition, i.e. ID50 1 mM for 2-FG, 6 mM for 2-CG and > 6 mM for 2-BG. Moreover, 2-FG was found to be more potent than 2-DG for both glycolytic inhibition and cytotoxicity. Conclusions: Overall, our in vitro results suggest that 2-FG is more potent than 2-DG in killing hypoxic tumor cells, and therefore may be more clinically effective when combined with standard chemotherapeutic protocols.

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Acknowledgment

Supported by NIH grant R01 CA037109 16, SPORE grant in Pancreatic Cancer P20 CA101936, a grant from The Morton and Angela Topfer Pancreatic Cancer Research Fund, and BST funds of Warsaw University.

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Authors and Affiliations

  1. School of Medicine and Sylvester Cancer Center, The University of Miami, Miami, FL, USA

    Theodore J. Lampidis, Metin Kurtoglu, Johnathan C. Maher, Huaping Liu, Awtar Krishan & Valerie Sheft

  2. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Slawomir Szymanski, Izabela Fokt & Waldemar Priebe

  3. Interdisciplinary Center for Mathematical and Computational Modeling, Warsaw University, Warsaw, Poland

    Witold R. Rudnicki, Krzysztof Ginalski & Bogdan Lesyng

  4. Department of Biophysics, Warsaw University, Warsaw, Poland

    Bogdan Lesyng

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  1. Theodore J. Lampidis
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  2. Metin Kurtoglu
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  3. Johnathan C. Maher
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  4. Huaping Liu
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  12. Waldemar Priebe
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Correspondence to Waldemar Priebe.

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Lampidis, T.J., Kurtoglu, M., Maher, J.C. et al. Efficacy of 2-halogen substituted d-glucose analogs in blocking glycolysis and killing “hypoxic tumor cells”. Cancer Chemother Pharmacol 58, 725–734 (2006). https://doi.org/10.1007/s00280-006-0207-8

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  • DOI: https://doi.org/10.1007/s00280-006-0207-8

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