Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions

Johnathan C. Maher, Awtar Krishan, Theodore Lampidis

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

Purpose: In order to investigate the hypothesis that cells found in hypoxic areas of solid tumors are more sensitive to glycolytic inhibitors than cells growing aerobically, we have previously characterized three distinct in vitro models (A, B and C) that simulate this condition. In all of the models it was shown that cells growing under hypoxic conditions are hypersensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). However, in those studies cytostatic and cytotoxic effects were not distinguished from one another. Since successful treatment of cancer includes not only slowing down but also actually killing tumor cells, studies were undertaken to assess the effects of 2-DG on cell cycle progression and cell death. Methods and results: Using flow cytometry and cell viability assays, it was found that 2-DG caused significantly greater cell cycle inhibition and cell death in all three hypoxic models as compared to aerobically growing control cells. In model A (a chemically induced model of hypoxia in which rhodamine-123 is used to block oxidative phosphorylation), 1200 μg/ml of 2-DG was shown to induce more cell cycle arrest in late S/G2 and more cell death than in the aerobic cell counterpart treated with 3600 μg/ml 2-DG. In ρ° cells which are genetically constructed to be unable to perform oxidative phosphorylation (model B), an even greater window of selectivity (more than tenfold) between hypoxic and aerobic cells was found when considering 2-DG's effects on cell cycle arrest and cell death. In the environmental model (model C), where cells were grown under reduced amounts of external oxygen (0.1%), hypersensitivity to the effects of 2-DG with respect to cell cycle arrest and cell death were also observed. Conclusions: Overall, these results indicate that cells growing under anaerobic conditions respond with greater sensitivity to the effects of 2-DG on cell cycle inhibition and cell death than those growing under aerobic conditions. This supports our contention that glycolytic inhibitors added to standard chemotherapeutic protocols should increase treatment efficacy by selectively killing the slow-growing cells, which are found in the hypoxic portions of solid tumors, while sparing most of the normal cells that are also slow-growing but are living under aerobic conditions.

Original languageEnglish
Pages (from-to)116-122
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume53
Issue number2
DOIs
StatePublished - Feb 1 2004

Fingerprint

Deoxyglucose
Cytotoxicity
Tumors
Cell Cycle
Cell death
Cells
Neoplasms
Cell Death
Cell Cycle Checkpoints
Oxidative Phosphorylation
Rhodamine 123
Flow cytometry
Cytostatic Agents
Assays
Oxygen
Cell Survival
Flow Cytometry
Hypersensitivity

Keywords

  • 2-Deoxy-D-glucose
  • Glycolysis
  • Hypoxia
  • Osteosarcoma
  • Oxidative phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. / Maher, Johnathan C.; Krishan, Awtar; Lampidis, Theodore.

In: Cancer Chemotherapy and Pharmacology, Vol. 53, No. 2, 01.02.2004, p. 116-122.

Research output: Contribution to journalArticle

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N2 - Purpose: In order to investigate the hypothesis that cells found in hypoxic areas of solid tumors are more sensitive to glycolytic inhibitors than cells growing aerobically, we have previously characterized three distinct in vitro models (A, B and C) that simulate this condition. In all of the models it was shown that cells growing under hypoxic conditions are hypersensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). However, in those studies cytostatic and cytotoxic effects were not distinguished from one another. Since successful treatment of cancer includes not only slowing down but also actually killing tumor cells, studies were undertaken to assess the effects of 2-DG on cell cycle progression and cell death. Methods and results: Using flow cytometry and cell viability assays, it was found that 2-DG caused significantly greater cell cycle inhibition and cell death in all three hypoxic models as compared to aerobically growing control cells. In model A (a chemically induced model of hypoxia in which rhodamine-123 is used to block oxidative phosphorylation), 1200 μg/ml of 2-DG was shown to induce more cell cycle arrest in late S/G2 and more cell death than in the aerobic cell counterpart treated with 3600 μg/ml 2-DG. In ρ° cells which are genetically constructed to be unable to perform oxidative phosphorylation (model B), an even greater window of selectivity (more than tenfold) between hypoxic and aerobic cells was found when considering 2-DG's effects on cell cycle arrest and cell death. In the environmental model (model C), where cells were grown under reduced amounts of external oxygen (0.1%), hypersensitivity to the effects of 2-DG with respect to cell cycle arrest and cell death were also observed. Conclusions: Overall, these results indicate that cells growing under anaerobic conditions respond with greater sensitivity to the effects of 2-DG on cell cycle inhibition and cell death than those growing under aerobic conditions. This supports our contention that glycolytic inhibitors added to standard chemotherapeutic protocols should increase treatment efficacy by selectively killing the slow-growing cells, which are found in the hypoxic portions of solid tumors, while sparing most of the normal cells that are also slow-growing but are living under aerobic conditions.

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