Radiosensitization by 6-aminonicotinamide and 2-deoxy-D-glucose in human cancer cells.

Abstract

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.

• Authors: R Varshney, Bs Dwarakanath, V Jain
• Journal: International journal of radiation biology (Int J Radiat Biol) Vol. 81 Issue 5 Pg. 397-408 (May 2005) ISSN: 0955-3002 [Print] England
• PMID: 16076755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites
• Radiation-Sensitizing Agents
• Teratogens
• 6-Aminonicotinamide
• Deoxyglucose

Topics

• 6-Aminonicotinamide (pharmacology)
• Antimetabolites (pharmacology)
• Apoptosis
• Brain Neoplasms (pathology)
• Carcinoma, Squamous Cell (pathology)
• Cell Death
• Cell Proliferation
• DNA Damage
• Deoxyglucose (pharmacology)
• Glioma (pathology)
• Humans
• Kinetics
• Radiation Tolerance
• Radiation-Sensitizing Agents (pharmacology)
• S Phase
• Teratogens (pharmacology)
• Tumor Cells, Cultured