DON, CONV and DONV—II. Inhibition of l-asparagine synthetase in vivo

Rosenbluth, Richard; Cooney, David A.; Jayaram, Hiremagalur N.; Milman, Harry A.; Homan, Elton R.

doi:10.1016/0006-2952(76)90189-1

Cited by 25 publications

(13 citation statements)

References 9 publications

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“…To determine whether autophagy is regulated by O-GlcNAcylation at basal levels in bladder cancer cell lines, we examined the autophagic flux in cells treated with DON or TG. As an inhibitor for different glutamine utilizing enzymes, DON inhibits the formation of UDP-GlcNAc, thereby reducing O-GlcNAcylation [26,27]. TG inhibits OGA, thereby promoting O-GlcNAcylation.…”

Section: O-glcnacylation Negatively Regulates Autophagy In Bladder Camentioning

confidence: 99%

Blockage of O-linked GlcNAcylation induces AMPK-dependent autophagy in bladder cancer cells

et al. 2020

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Background: High levels of the post-translational modification O-GlcNAcylation (O-GlcNAc) are found in multiple cancers, including bladder cancer. Autophagy, which can be induced by stress from post-translational modifications, plays a critical role in maintaining cellular homeostasis and regulating tumorigenesis. The impact of O-GlcNAcylation on autophagy in bladder cancer remains unclear. Here, we evaluate the change in autophagic activity in response to O-GlcNAcylation and explore the potential mechanisms. Methods: O-GlcNAcylation levels in bladder cancer cells were altered through pharmacological or genetic manipulations: treating with 6-diazo-5-oxo-norleucine (DON) or thiamet-G (TG) or up-and downregulation of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA). Autophagy was determined using fluorescence microscopy and western blotting. Co-immunoprecipitation (Co-IP) assays were performed to evaluate whether the autophagy regulator AMP-activated protein kinase (AMPK) was O-GlcNAc modified. Results: Cellular autophagic flux was strikingly enhanced as a result of O-GlcNAcylation suppression, whereas it decreased at high O-GlcNAcylation levels. Phosphorylation of AMPK increased after the suppression of O-GlcNAcylation. We found that O-GlcNAcylation of AMPK suppressed the activity of this regulator, thereby inhibiting ULK1 activity and autophagy. Conclusion: We characterized a new function of O-GlcNAcylation in the suppression of autophagy via regulation of AMPK.

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Section: O-glcnacylation Negatively Regulates Autophagy In Bladder Camentioning

confidence: 99%

Blockage of O-linked GlcNAcylation induces AMPK-dependent autophagy in bladder cancer cells

et al. 2020

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“…As an analog of glutamine, DON has been used as an inhibitor of glutamine utilizing enzymes such as carbamoyl phosphate synthase (CAD), CTP synthase (CTPS), FGAR amidotransferase, guanosine monophosphate synthetase (GMPS), PRPP amidotransferase, NAD synthase, asparagine synthase, and glutaminase. These enzymes are used in several important metabolic pathways such as the purine, pyrimidine, and amino acid synthesis as well as a coenzyme of the electron transport chain and in the first step of glutaminolysis [ 89 – 95 ].…”

Section: Don (6-diazo-5-oxo-l-norleucine)mentioning

confidence: 99%

Reviving Lonidamine and 6-Diazo-5-oxo-L-norleucine to Be Used in Combination for Metabolic Cancer Therapy

Cervantes-Madrid

Romero

Dueñas‐González

2015

BioMed Research International

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Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural targets for cancer therapy. Currently, a number of newer compounds to block glycolysis and glutaminolysis are being developed; nevertheless, lonidamine and 6-diazo-5-oxo-L-norleucine (DON) are two old drugs well characterized as inhibitors of glycolysis and glutaminolysis, respectively, whose clinical development was abandoned years ago when the importance of cancer metabolism was not fully appreciated and clinical trial methodology was less developed. In this review, a PubMed search using the words lonidamine and 6-diazo-5-oxo-L-norleucine (DON) was undertaken to analyse existing information on the preclinical and clinical studies of these drugs for cancer treatment. Data show that they exhibit antitumor effects; besides there is also the suggestion that they are synergistic. We conclude that lonidamine and DON are safe and potentially effective drugs that need to be reevaluated in combination as metabolic therapy of cancer.

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“…Measurement ofL-asparaginase activity L-Asparaginase activity was assessed by a radiometric procedure as described by Rosenbluth et al (1976).…”

Section: Measurement Of L-glutaminase Activitymentioning

confidence: 99%

Partial purification and properties of l-asparagine synthetase from mouse pancreas

Milman

Cooney

1979

Biochemical Journal

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l-Asparagine synthetase was partially purified from mouse pancreas to a final mean specific activity of 0.10 unit/mg of protein. The enzyme exhibited an l-glutaminase activity which was not affected by l-asparate, NH(4)Cl, ATP-MgCl(2), l-glutamate, AMP (sodium salt) or sodium pyrophosphate. The l-glutamine-dependent l-asparagine synthetase activity of the partially purified enzyme from mouse pancreas was markedly decreased by freezing for 7 days at -87 degrees C in the presence of 1mm-dithiothreitol, but effectively protected from inactivation by high concentrations (10mm) of the thiol reagent. The l-glutaminase activity of the enzyme was inhibited by antagonists of l-glutamine (e.g. 6-diazo-5-oxo-l-norleucine, 5-chloro-4-oxo-l-norvaline, 5-diazo-4-oxo-l-norvaline and NSC-163501) and thiol-reactive compounds (e.g. 2-amino-4-arsenophenol hydrochloride, maleimide, mucochloric acid and ZnCl(2)), but not by aminomalonic acid, the next lower homologue of l-aspartate, nor by l-homoserine beta-adenylate, an analogue of the presumed transitory covalent intermediate. The complete forward reaction catalysed by l-asparagine synthetase from mouse pancreas appears to be irreversible and essentially stoicheiometric under the conditions examined. Mouse pancreas contains a proteolytic inhibitor of l-asparagine synthetase separable from the enzyme by ion-exchange column chromatography. The inhibitor is activated by incubation at 4 degrees C for 110h and inactivated by soya-bean trypsin inhibitor, di-isopropyl phosphorofluoridate and boiling.

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DON, CONV and DONV—II. Inhibition of l-asparagine synthetase in vivo

Cited by 25 publications

References 9 publications

Blockage of O-linked GlcNAcylation induces AMPK-dependent autophagy in bladder cancer cells

Blockage of O-linked GlcNAcylation induces AMPK-dependent autophagy in bladder cancer cells

Reviving Lonidamine and 6-Diazo-5-oxo-L-norleucine to Be Used in Combination for Metabolic Cancer Therapy

Partial purification and properties of l-asparagine synthetase from mouse pancreas

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