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BioMed Research International 2015Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural... (Review)
Review
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.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Diazooxonorleucine; Humans; Indazoles; Neoplasms
PubMed: 26425550
DOI: 10.1155/2015/690492 -
Cancer Research Feb 2024A promising approach to treat solid tumors involves disrupting their reliance on glutamine, a key component for various metabolic processes. Traditional attempts using...
A promising approach to treat solid tumors involves disrupting their reliance on glutamine, a key component for various metabolic processes. Traditional attempts using glutamine inhibitors like 6-diazo-5-oxo-L-norleucine (DON) and CB-839 were unsuccessful, but new hope arises with DRP-104, a prodrug of DON. This compound effectively targets tumor metabolism while minimizing side effects. In a recent study published in Nature Cancer, Encarnación-Rosado and colleagues demonstrated in preclinical models that pancreatic ductal adenocarcinoma (PDAC) responds well to DRP-104, although tumors adapt through the MEK/ERK signaling pathway, which can be countered by the MEK inhibitor trametinib. In a related study, Recouvreux and colleagues found that DON is effective against pancreatic tumors, revealing that PDAC tumors upregulate asparagine synthesis in response to DON, making them susceptible to asparaginase treatment. Both studies underscore the potential of inhibiting glutamine metabolism and adaptive pathways as a promising strategy against PDAC. These findings pave the way for upcoming clinical trials utilizing DRP-104 and similar glutamine antagonists in the battle against solid tumors.
Topics: Humans; Glutamine; Diazooxonorleucine; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Enzyme Inhibitors; Mitogen-Activated Protein Kinase Kinases
PubMed: 38117482
DOI: 10.1158/0008-5472.CAN-23-3954 -
Journal of Controlled Release :... Apr 2024Modulating the metabolism of cancer cells, immune cells, or both is a promising strategy to potentiate cancer immunotherapy in the nutrient-competitive tumor...
Modulating the metabolism of cancer cells, immune cells, or both is a promising strategy to potentiate cancer immunotherapy in the nutrient-competitive tumor microenvironment. Glutamine has emerged as an ideal target as cancer cells highly rely on glutamine for replenishing the tricarboxylic acid cycle in the process of aerobic glycolysis. However, non-specific glutamine restriction may induce adverse effects in unconcerned tissues and therefore glutamine inhibitors have achieved limited success in the clinic so far. Here we report the synthesis and evaluation of a redox-responsive prodrug of 6-Diazo-5-oxo-L-norleucine (redox-DON) for tumor-targeted glutamine inhibition. When applied to treat mice bearing subcutaneous CT26 mouse colon carcinoma, redox-DON exhibited equivalent antitumor efficacy but a greatly improved safety profile, particularly, in spleen and gastrointestinal tract, as compared to the state-of-the-art DON prodrug, JHU083. Furthermore, redox-DON synergized with checkpoint blockade antibodies leading to durable cures in tumor-bearing mice. Our results suggest that redox-DON is a safe and effective therapeutic for tumor-targeted glutamine inhibition showing promise for enhanced metabolic modulatory immunotherapy. The approach of reversible chemical modification may be generalized to other metabolic modulatory drugs that suffer from overt toxicity.
Topics: Animals; Mice; Diazooxonorleucine; Prodrugs; Glutamine; Colonic Neoplasms; Oxidation-Reduction; Tumor Microenvironment
PubMed: 38403173
DOI: 10.1016/j.jconrel.2024.02.031 -
Cellular Immunology Dec 2021Infection of the cornea with HSV results in an immune-inflammatory reaction orchestrated by proinflammatory T cells that is a major cause of human vision impairment. The...
Infection of the cornea with HSV results in an immune-inflammatory reaction orchestrated by proinflammatory T cells that is a major cause of human vision impairment. The severity of lesions can be reduced if the representation of inflammatory T cells is changed to increase the presence of T cells with regulatory function. This report shows that inhibiting glutamine metabolism using 6-Diazo-5-oxo-l-norleucine (DON) administered via intraperitoneal (IP) starting 6 days after ocular infection and continued until day 15 significantly reduced the severity of herpetic stromal keratitis lesions. The therapy resulted in reduced neutrophils, macrophages as well proinflammatory CD4 Th1 and Th17 T cells in the cornea, but had no effect on levels of regulatory T cells. A similar change in the representation of inflammatory and regulatory T cells occurred in the trigeminal ganglion (TG) the site where HSV infection establishes latency. Glutamine metabolism was shown to be required for the in-vitro optimal induction of both Th1 and Th17 T cells but not for the induction of Treg that were increased when glutamine metabolism was inhibited. Inhibiting glutamine metabolism also changed the ability of latently infected TG cells from animals previously infected with HSV to reactivate and produce infectious virus.
Topics: Animals; Diazooxonorleucine; Glutamine; Keratitis, Herpetic; Latent Infection; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; T-Lymphocytes; Trigeminal Ganglion; Virus Activation; Virus Latency
PubMed: 34678554
DOI: 10.1016/j.cellimm.2021.104450 -
Discover Oncology Feb 2023Carbohydrate antigen 19-9 (CA19-9) is the most widely used biomarker for pancreatic cancer. Since CA19-9 closely correlates with patient outcome and tumor stage in...
BACKGROUND
Carbohydrate antigen 19-9 (CA19-9) is the most widely used biomarker for pancreatic cancer. Since CA19-9 closely correlates with patient outcome and tumor stage in pancreatic cancer, the deciphering of CA19-9 biosynthesis provides a potential clue for treatment.
METHODS
Concentration of amino acids was detected by ultrahigh-performance liquid chromatography tandem mass spectrometry. Metabolic flux of glutamine was examined by isotope tracing untargeted metabolomics. Label-free quantitative N-glycosylation proteomics was used to examine N-glycosylation alterations.
RESULTS
Among all amino acids, glutamine was higher in CA19-9-high pancreatic cancers (> 37 U/mL, 66 cases) than in CA19-9-normal clinical specimens (≤ 37 U/mL, 37 cases). The glutamine concentration in clinical specimens was positively correlated with liver metastasis or lymphovascular invasion. Glutamine blockade using diazooxonorleucine suppressed pancreatic cancer growth and intraperitoneal and lymphatic metastasis. Glutamine promotes O-GlcNAcylation, protein glycosylation, and CA19-9 biosynthesis through the hexosamine biosynthetic pathway. UDP-N-acetylglucosamine (UDP-GlcNAc) levels correlated with the glutamine influx through hexosamine biosynthetic pathway and supported CA19-9 biosynthesis.
CONCLUSIONS
Glutamine is a substrate for CA19-9 biosynthesis in pancreatic cancer. Glutamine blockade may be a potential therapeutic strategy for pancreatic cancer.
PubMed: 36797531
DOI: 10.1007/s12672-023-00628-z -
Azaserine, DON, and azotomycin: three diazo analogs of L-glutamine with clinical antitumor activity.Cancer Treatment Reports Jun 1979A review of the clinical data on azaserine, DON, and azotomycin reveals that these agents have limited but definite antitumor activity. All three drugs are analogs of... (Review)
Review
A review of the clinical data on azaserine, DON, and azotomycin reveals that these agents have limited but definite antitumor activity. All three drugs are analogs of L-glutamine and contain a diazo group. They have been studied as single agents in a wide variety of human malignancies and have also been included in trials using combination chemotherapy. Most of these studies were performed early in the history of clinical trials and, therefore, the method of reporting results and the evaluation criteria were quite different from those in use today. A renewed interest in these agents has been triggered by the remarkable activity of DON and azotomycin against human tumor lines implanted into nude mice. On the basis of this activity and the clinical data we have compiled, we feel that new clinical trials with these agents are warranted.
Topics: Animals; Antineoplastic Agents; Azaserine; Azo Compounds; Colonic Neoplasms; Diazooxonorleucine; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Transplantation, Heterologous
PubMed: 380801
DOI: No ID Found -
Biochemistry Feb 1978Acinetobactor glutaminase-asparaginase was treated with [6-14C]diazo-5-oxonorleucine, reduced with sodium borohydride, and cleaved with cyanogen bromide. Radioactivity... (Comparative Study)
Comparative Study
Acinetobactor glutaminase-asparaginase was treated with [6-14C]diazo-5-oxonorleucine, reduced with sodium borohydride, and cleaved with cyanogen bromide. Radioactivity was present only in a 96-residue-N-terminal peptide which eluted as the second peptide peak on Sephadex G-50. Radioactivity was released with the threonine in position 12 during automatic sequencing of this peptide. The amino acid sequence of a 60-residue tn-terminal segment and a 16-residue C-terminal segment of this peptide was determined. Pseudomonas 7 A glutaminase-asparaginase was treated with [6-14C]diazo-5-oxonorleucine and reduced with sodium borohydride. Radioactivity was released with the threonine in residue 20 during automatic sequencing of the whole enzyme. Analysis of 26 N-terminal residues showed that an 8-residue segment containing the radioactive threonine was identical with that in Acinetobacter glutaminase-asparaginase and in Escherichia coli asparaginase. Additional identical residues were noted in the N-terminal regions of these enzymes.
Topics: Acinetobacter; Amino Acid Sequence; Amino Acids; Asparaginase; Azo Compounds; Binding Sites; Diazooxonorleucine; Glutaminase; Protein Binding; Pseudomonas; Species Specificity
PubMed: 619999
DOI: 10.1021/bi00596a005 -
Haematologia 1970
Topics: Adult; Amidohydrolases; Anemia, Hemolytic, Congenital Nonspherocytic; Anti-Bacterial Agents; Azo Compounds; Carbon Isotopes; Chromatography, Paper; Diazooxonorleucine; Erythrocytes; Ethylmaleimide; Glycolysis; Humans; NAD; Niacinamide; Nicotinic Acids; Nucleotides; Phospholipids; Pyridines
PubMed: 4330785
DOI: No ID Found -
Advances in Pharmacology and... 1970
Review
Topics: Adult; Aminobutyrates; Animals; Asparaginase; Azaserine; Azo Compounds; Child; Diazooxonorleucine; Drug Combinations; Drug Interactions; Glutamate-Ammonia Ligase; Glutaminase; Glutamine; Humans; Hydroxylysine; Leukemia; Leukemia L1210; Liver; Methionine Sulfoximine; Mice; Neoplasms; RNA, Transfer; Rats
PubMed: 4400179
DOI: 10.1016/s1054-3589(08)60594-3 -
Disaster Medicine and Public Health... Nov 2023Search and rescue teams and Antarctic research groups use protective cold-water anti-exposure suits (AES) when cruising on Zodiacs. Extremity tourniquet (ET)...
Search and rescue teams and Antarctic research groups use protective cold-water anti-exposure suits (AES) when cruising on Zodiacs. Extremity tourniquet (ET) self-application (SA) donned with AESs has not been previously studied. Our study therefore assessed the SA of 5 commercial ETs (CAT, OMNA, RATS, RMT, and SWAT-T) among 15 volunteers who donned these suits. Tourniquet's SA ability, ease of SA, tolerance, and tourniquet preference were measured. All ETs tested were self-applied to the upper extremity except for the SWAT, which was self-applied with the rest to the lower extremity. Ease- of- SA mean values were compared using the Friedman and Durbin-Conover post hoc tests < 0.001). Regarding the upper extremity, OMNA achieved the highest score of 8.5 out of 10, while RMT, and SWAT received lower scores than other options 0.001). For lower extremities, SWAT was found to be inferior to other options 0.01). Overall, OMNA was the best performer. The RATS showed significantly lower tolerance than the other groups in repeated- measures ANOVA with a Tukey post hoc test 0.01). Additionally, out of the 5 ETs tested, 60% of subjects preferred OMNA. The study concluded that SA commercial ETs are feasible over cold-water anti-exposure suits in the Antarctic climate.
Topics: Humans; Antarctic Regions; Tourniquets; Hemorrhage; Extremities; Diazooxonorleucine; Water
PubMed: 37937358
DOI: 10.1017/dmp.2023.179