Quantitation of metabolic and radiobiological effects of 6-aminonicotinamide in RIF-1 tumor cells in vitro.
6-Aminonicotinamide (6AN) can be metabolized to 6-amino-NAD(P+), a competitive inhibitor of NAD(P+)-requiring processes, especially the pentose phosphate pathway (PPP) enzyme, 6-phosphogluconate dehydrogenase. The effect of 6AN on the flux of 1 and 6 13C-labeled glucose to lactate, via glycolysis and the PPP, was investigated using 1H-nuclear magnetic resonance. These studies showed that 6AN as a single agent caused a significant 89% (P < 0.0001) inhibition of glycolytic flux but had no detectable effect on the PPP. 31P-nuclear magnetic resonance studies of perifused RIF-1 cells indicated that 4 h of exposure to 6AN were sufficient to cause significant accumulation of 6-phosphogluconate, the substrate for this enzyme (P < 0.0001). A significant reduction in the phosphocreatine: inorganic phosphate ratio was observed under conditions that led to accumulation of 6-phosphogluconate (P < 0.006). Accumulation of 6-phosphogluconate and subsequent reduction in phosphocreatine correlated with significant potentiation of 6 Gy of irradiation by 6AN. These results suggest that the radiation enhancement effect of 6AN may be due to inhibition of glycolysis (mediated by 6-phosphogluconate) and the associated reduction in high-energy phosphates. Additional studies analyzing the metabolic effects of 6AN in combination with radiation are necessary to determine the role of inhibition of the PPP in 6AN enhancement of radiation.
Street
J C
JC
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Alfieri
A A
AA
Koutcher
J A
JA
D015120:6-Aminonicotinamide / Q000494:pharmacology*; D005720:Gamma Rays; D006019:Glycolysis / Q000187:drug effects*; D007773:Lactates / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D010725:Phosphocreatine / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D007773:Lactates; D011838:Radiation-Sensitizing Agents; D010725:Phosphocreatine; D015120:6-Aminonicotinamide