Modulation of cellular radiation responses by 2-deoxy-D-glucose and other glycolytic inhibitors: implications for cancer therapy

Abstract

Background: 2-Deoxy-D-glucose (2-DG), a glycolytic inhibitor, was observed earlier to increase DNA, chromosomal, and cellular damage in tumor cells, by inhibiting energy-dependent repair processes. Lonidamine (LND) selectively inhibits glycolysis in cancer cells. It damages the condensed mitochondria in these cells, impairing thereby the activity of hexokinase (predominantly attached to the outer mitochondrial membranes). It inhibits repair of radiation-induced potentially lethal cellular damage in HeLa and Chinese hamster (HA-1) cells. However, other than a preliminary study on human glioma (BMG-1) cells in this laboratory, the effects of LND on radiation-induced cytogenetic damage have not been reported earlier.

Aims: These studies were carried out to investigate the effects of LND and 2-DG on cell proliferation, viability, and radiation response in the same human glioma cell line, under identical conditions. The respective drug concentrations were selected on the basis of earlier studies.

Materials and methods: Human glioma (U373MG) cells were grown in the presence of LND or 2-DG for 2 days. Proliferation response and viability of U373MG human glioma cells were studied by cell counts and uptake of trypan blue dye. Radiosensitization (increase in micronuclei formation) was studied after short-term (4 h postirradiation) drug treatments.

Observations: Both the drugs (1) inhibited proliferation response in a concentration-dependent manner; (2) did not induce micronuclei formation in the unirradiated cells; and (3) significantly increased radiation-induced micronuclei formation at nontoxic concentrations.

Conclusions: These data suggest that the short-term presence of either lonidamine or 2-DG-at clinically relevant and nontoxic concentrations-could increase the treatment response of malignant gliomas at optimum radiation doses, reducing thereby the side effects of radiotherapy.