Kalia Vijay K, Prabhakara S, Narayanan Vidya
Department of Biophysics, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
J Cancer Res Ther. 2009 Sep;5 Suppl 1:S57-60. doi: 10.4103/0973-1482.55145.
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.
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.
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.
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.
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.
2-脱氧-D-葡萄糖（2-DG）是一种糖酵解抑制剂，早期观察发现它通过抑制能量依赖的修复过程，增加肿瘤细胞中的DNA、染色体和细胞损伤。氯尼达明（LND）选择性抑制癌细胞中的糖酵解。它破坏这些细胞中浓缩的线粒体，从而损害己糖激酶（主要附着在线粒体外膜）的活性。它抑制HeLa细胞和中国仓鼠（HA-1）细胞中辐射诱导的潜在致死性细胞损伤的修复。然而，除了本实验室对人胶质瘤（BMG-1）细胞的初步研究外，LND对辐射诱导的细胞遗传学损伤的影响此前尚未见报道。
开展这些研究以在相同条件下，研究LND和2-DG对同一人胶质瘤细胞系的细胞增殖、活力及辐射反应的影响。根据早期研究选择各自的药物浓度。
人胶质瘤（U373MG）细胞在LND或2-DG存在的情况下培养2天。通过细胞计数和台盼蓝染料摄取研究U373MG人胶质瘤细胞的增殖反应和活力。在短期（照射后4小时）药物处理后研究放射增敏作用（微核形成增加）。
两种药物均（1）以浓度依赖的方式抑制增殖反应；（2）在未照射的细胞中未诱导微核形成；（3）在无毒浓度下显著增加辐射诱导的微核形成。
这些数据表明，在临床相关且无毒的浓度下，短期存在氯尼达明或2-DG可在最佳辐射剂量下增加恶性胶质瘤的治疗反应，从而降低放疗的副作用。
