Radiosensitization by 6-aminonicotinamide and 2-deoxy-D-glucose in human cancer cells.
The aim was to exploit simultaneous inhibition of glycolytic and pentose phosphate pathways of energy production for radiosensitization using 2-deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) in transformed mammalian cells. Two human tumour cell lines (cerebral glioma, BMG-1 and squamous carcinoma cells 4197) were investigated. 2-DG and/or 6-AN added at the time of irradiation were present for 4 h after radiation. Radiation-induced cell death (macrocolony assay), cytogenetic damage (micronuclei formation), cell cycle delay (bromodeoxyuridne (BrdU) pulse chase), apoptosis (externalization of phosphotidylserine (PS) by annexin V), chromatin-bound proliferation cell nuclear antigen (PCNA) and cellular glutathione (GSH) levels were investigated as parameters of radiation response. The presence of 2-DG (5 mM) during and for 4 h after irradiation increased the radiation-induced micronuclei formation and cell death, and caused a time-dependent decrease in GSH levels in BMG-1 cells while no significant effects could be observed in 4197 cells. 6-AN (5 microM) enhanced the radiosensitivity of both cell lines and reduced the GSH content by nearly 50% in gamma-irradiated 4197 cells. Combining 2-DG and 6-AN caused a profound decrease in the GSH content and enhanced the radiation damage in both the cell lines by increasing mitotic and apoptotic cell death. Further, the combination (2-DG + 6-AN) enhanced the radiation-induced G2 block, besides arresting cells in S phase and inhibited the recruitment of PCNA. The combination of 2-DG and 6-AN enhances radiation damage by modifying damage response pathways and has the potential for improving radiotherapy of cancer.
Varshney
R
R
Institute of Nuclear Medicine & Allied Sciences, Delhi, India. rajeev@inmas.org
Dwarakanath
Bs
B
Jain
V
V
D015120:6-Aminonicotinamide / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D016923:Cell Death; D049109:Cell Proliferation; D004249:DNA Damage; D003847:Deoxyglucose / Q000494:pharmacology*; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007700:Kinetics; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016196:S Phase; D013723:Teratogens / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D011838:Radiation-Sensitizing Agents; D013723:Teratogens; D015120:6-Aminonicotinamide; D003847:Deoxyglucose