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Efficacy of 2-halogen Substituted D-glucose Analogs in Blocking Glycolysis and Killing "Hypoxic Tumor Cells"

Efficacy of 2-halogen Substituted D-glucose Analogs in Blocking Glycolysis and Killing "Hypoxic Tumor Cells"

Theodore J Lampidis, Metin Kurtoglu, Johnathan C Maher, Huaping Liu, Awtar Krishan, Valerie Sheft, Slawomir Szymanski, Izabela Fokt, Witold R Rudnicki, Krzysztof Ginalski, Bogdan Lesyng, Waldemar Priebe

Cancer Chemother Pharmacol. 2006 Dec;58(6):725-34.

PMID: 16555088

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP14685791-A	2-Chloro-2-deoxy-D-glucose		14685-79-1	Price

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