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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.
AuthorsR Varshney, Bs Dwarakanath, V Jain
JournalInternational journal of radiation biology (Int J Radiat Biol) Vol. 81 Issue 5 Pg. 397-408 (May 2005) ISSN: 0955-3002 [Print] England
PMID16076755 (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

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