2-deoxy-D-glucose enhances the cytotoxicity of topoisomerase inhibitors in human tumor cell lines.
Resistance of tumors due to restricted drug accumulation and reversal of DNA lesions in tumor cells as well as normal tissue toxicity limit the efficacy of topoisomerase inhibition based anticancer drugs. It has been proposed that selective inhibition of energy dependent repair processes and enhanced retention of drug in cancer cells can significantly improve the therapeutic efficacy. The purpose of these studies was to verify this proposition by investigating the effects of 2-deoxy-D-glucose (2-DG) an inhibitor of the glycolytic ATP production on the cytotoxicity of certain topoisomerase inhibitors in human tumor cell lines. Human glioma (BMG-1 and U-87) and squamous carcinoma (4197 and 4451) cell lines were investigated with topo-poisons like etoposide (topo II inhibitor), camptothecin (topo I inhibitor) and hoechst-33342 (topo I and II inhibitor). DNA damage induction (halo assay), cell survival (macro colony assay), cytogenetic damage (micronuclei) and apoptosis (morphological analysis) were investigated. Presence of 2-DG for 2 h following exposure to the topoisomerase inhibitors enhanced the cell death (macro colony assay) in a concentration dependent manner and a 2-3-fold increase was observed at 5 mM (equimolar with glucose). Halo assay revealed that 2-DG inhibited the reversal of cleavable complex leading to the accumulation of DNA strand breaks. Under these conditions 2-DG enhanced the drug-induced micronuclei formation by nearly 2 folds with etoposide and hoechst-33342 and a 4-fold increase in delayed apoptosis was observed in case of etoposide. These results clearly demonstrate that presence of 2-DG for a few hours following exposure to topo-inhibitors enhances the cytotoxicity, primarily by increasing the cytogenetic damage.
Dwarakanath
B S
BS
Institute of Nuclear Medicine and Allied Sciences, Brig. S.K. Mazumdar Marg, Delhi, India. bs@inmas.org
Khaitan
Divya
D
Ravindranath
T
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000963:Antimetabolites / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology*; D002166:Camptothecin / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002470:Cell Survival; D004249:DNA Damage; D003847:Deoxyglucose / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005910:Glioma / Q000473:pathology*; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D059003:Topoisomerase Inhibitors; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011838:Radiation-Sensitizing Agents; D059003:Topoisomerase Inhibitors; D005047:Etoposide; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; C017807:bisbenzimide ethoxide trihydrochloride; D002166:Camptothecin