Efficacy of 2-halogen substituted D-glucose analogs in blocking glycolysis and killing "hypoxic tumor cells"

Theodore 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)725-734
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume58
Issue number6
DOIs
StatePublished - Dec 1 2006

Fingerprint

Halogens
Deoxyglucose
Glycolysis
Tumors
Cells
Glucose
Hexokinase
Neoplasms
Clinical Trials, Phase I
Quantitative Structure-Activity Relationship
Trypan Blue
Molecular interactions
Flow cytometry
Fluorodeoxyglucose F18
Cytotoxicity
Binding energy
Computer Simulation
Toxicity
Lactic Acid
Assays

Keywords

  • 2-Deoxy-D-glucose
  • 2-Fluoro-2-deoxy-D-glucose
  • Antitumor activity
  • Glycolysis
  • Hypoxia

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Efficacy of 2-halogen substituted D-glucose analogs in blocking glycolysis and killing "hypoxic tumor cells". / Lampidis, Theodore; Kurtoglu, Metin; Maher, Johnathan C.; Liu, Huaping; Krishan, Awtar; Sheft, Valerie; Szymanski, Slawomir; Fokt, Izabela; Rudnicki, Witold R.; Ginalski, Krzysztof; Lesyng, Bogdan; Priebe, Waldemar.

In: Cancer Chemotherapy and Pharmacology, Vol. 58, No. 6, 01.12.2006, p. 725-734.

Research output: Contribution to journalArticle

Lampidis, T, Kurtoglu, M, Maher, JC, Liu, H, Krishan, A, Sheft, V, Szymanski, S, Fokt, I, Rudnicki, WR, Ginalski, K, Lesyng, B & Priebe, W 2006, 'Efficacy of 2-halogen substituted D-glucose analogs in blocking glycolysis and killing "hypoxic tumor cells"', Cancer Chemotherapy and Pharmacology, vol. 58, no. 6, pp. 725-734. https://doi.org/10.1007/s00280-006-0207-8
Lampidis, Theodore ; Kurtoglu, Metin ; Maher, Johnathan C. ; Liu, Huaping ; Krishan, Awtar ; Sheft, Valerie ; Szymanski, Slawomir ; Fokt, Izabela ; Rudnicki, Witold R. ; Ginalski, Krzysztof ; Lesyng, Bogdan ; Priebe, Waldemar. / Efficacy of 2-halogen substituted D-glucose analogs in blocking glycolysis and killing "hypoxic tumor cells". In: Cancer Chemotherapy and Pharmacology. 2006 ; Vol. 58, No. 6. pp. 725-734.
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AU - Liu, Huaping

AU - Krishan, Awtar

AU - Sheft, Valerie

AU - Szymanski, Slawomir

AU - Fokt, Izabela

AU - Rudnicki, Witold R.

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N2 - 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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