(13)C and (31)P NMR investigation of effect of 6-aminonicotinamide on metabolism of RIF-1 tumor cells in vitro Journal Article

  

Authors:	Street, J. C.; Mahmood, U.; Ballon, D.; Alfieri, A. A.; Koutcher, J. A.
Article Title:	(13)C and (31)P NMR investigation of effect of 6-aminonicotinamide on metabolism of RIF-1 tumor cells in vitro
Abstract:	The effect of 6-aminonicotinamide on the metabolism of RIF-1 tumor cells was investigated using 13C and 31P NMR spectroscopy. 6-Aminonicotinamide can be metabolized to 6-amino-NAD(P), a competitive inhibitor of NAD(P)-requiring processes. 40 μM 6-aminonicotinamide led to an inhibition of 6-phosphogluconate dehy-drogenase and an accumulation of 6-phosphogluconate. A subsequent accumulation of the 6-phosphogluconate precursor 6-phosphoglucono-δ-lactone was observed in the 13C NMR spectrum. These metabolites were shown to be intracellular, although a small amount of leakage of 6-phosphoglucono-δ-lactone occurred. The intracellular concentrations of 6-phosphogluconate and 6-phosphoglucono-δ-lactone were 1.9 ± 0.8 μmol/108 cells (±1 standard deviation) and 0.8 ± 0.4 μmol/108 cells, respectively, after 15 h. Glucose utilization and lactate production were significantly inhibited by 6-aminonicotinamide (both p < 0.05), indicating inhibition of glycolysis. 31P NMR data showed that phosphocreatine was significantly depleted in cells exposed to 6-aminonicotinamide (p < 0.05). Exposure of RIF-1 cells to 6-aminonicotinamide prior to 3- or 6-Gy x-irradiation induced a supra-additive cell kill, indicating that 6-aminonicotinamide is acting as a radiosensitizer. There was no effect of 6-aminonicotinamide alone or when the drug was given postradiation, suggesting that its mechanism of action may be by inhibition of radiation-induced repair.
Keywords:	controlled study; dose response; methodology; animal; metabolism; animals; cell survival; cell line; cancer cell culture; drug effect; drug screening; dose-response relationship, drug; tumor cells, cultured; radiation injury; time; time factors; fibrosarcoma; kinetics; drug mechanism; cell culture; neoplasms, radiation-induced; magnetic resonance spectroscopy; nuclear magnetic resonance spectroscopy; glucose; phosphorus nuclear magnetic resonance; glycolysis; x irradiation; x ray; carbon; carbon isotopes; phosphorus; carbon nuclear magnetic resonance; x-rays; glucose metabolism; glucose utilization; 6 aminonicotinamide; priority journal; article; 6-aminonicotinamide
Journal Title:	Journal of Biological Chemistry
Volume:	271
Issue:	8
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Date Published:	1996-02-23
Start Page:	4113
End Page:	4119
Language:	English
PUBMED:	8626749
PROVIDER:	scopus
DOI:	10.1074/jbc.271.8.4113
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-0029671453&partnerID=40&md5=cfb946e0ca0819f2f79d1e9181cdbd63
Notes:	Article -- Export Date: 22 November 2017 -- Source: Scopus

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