Greater cell cycle inhibition and cytotoxicity ind

Authors: Johnathan C Maher Awtar Krishan Theodore J Lampidis

Publish Date: 2003/11/07

Volume: 53, Issue: 2, Pages: 116-122

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Abstract

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 2deoxydglucose 2DG 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 2DG on cell cycle progression and cell deathUsing flow cytometry and cell viability assays it was found that 2DG 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 rhodamine123 is used to block oxidative phosphorylation 1200 μg/ml of 2DG 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 2DG In ρ0 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 2DG’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 01 hypersensitivity to the effects of 2DG with respect to cell cycle arrest and cell death were also observedOverall these results indicate that cells growing under anaerobic conditions respond with greater sensitivity to the effects of 2DG 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 slowgrowing cells which are found in the hypoxic portions of solid tumors while sparing most of the normal cells that are also slowgrowing but are living under aerobic conditions

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