Erschienen in:
01.12.2006 | Original Article
Efficacy of 2-halogen substituted d-glucose analogs in blocking glycolysis and killing “hypoxic tumor cells”
verfasst von:
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
Erschienen in:
Cancer Chemotherapy and Pharmacology
|
Ausgabe 6/2006
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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.