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Biochemical Pharmacology Apr 2024The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this... (Review)
Review
The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this liver-specific pathway induced either by primary genetic defects or by secondary causes, namely those associated with hepatic disease or drug administration, may result in serious clinical consequences. Urea cycle disorders (UCD) and certain organic acidurias are the major groups of inherited rare diseases manifested with hyperammonemia (HA) with UC dysregulation. Importantly, several commonly prescribed drugs, including antiepileptics in monotherapy or polytherapy from carbamazepine to valproic acid or specific antineoplastic agents such as asparaginase or 5-fluorouracil may be associated with HA by mechanisms not fully elucidated. HA, disclosing an imbalance between ammoniagenesis and ammonia disposal via the UC, can evolve to encephalopathy which may lead to significant morbidity and central nervous system damage. This review will focus on biochemical mechanisms related with HA emphasizing some poorly understood perspectives behind the disruption of the UC and mitochondrial energy metabolism, namely: i) changes in acetyl-CoA or NAD levels in subcellular compartments; ii) post-translational modifications of key UC-related enzymes, namely acetylation, potentially affecting their catalytic activity; iii) the mitochondrial sirtuins-mediated role in ureagenesis. Moreover, the main UCD associated with HA will be summarized to highlight the relevance of investigating possible genetic mutations to account for unexpected HA during certain pharmacological therapies. The ammonia-induced effects should be avoided or overcome as part of safer therapeutic strategies to protect patients under treatment with drugs that may be potentially associated with HA.
Topics: Humans; Hyperammonemia; Ammonia; Liver Diseases; Urea
PubMed: 38307136
DOI: 10.1016/j.bcp.2024.116034 -
Cancers Nov 2023The multidrug nature of anticancer treatment and different treatment protocols used in the studies are likely to be a major limitation in establishing real risk factors...
The multidrug nature of anticancer treatment and different treatment protocols used in the studies are likely to be a major limitation in establishing real risk factors determining the occurrence of dental abnormalities. The authors aimed to establish a relationship between the duration and the dose of chemotherapy and the number of tooth adverse effects in the group receiving the same treatment. Of the 40 anticancer therapy recipients who attended the outpatient dental clinic, 7 leukemia survivors receiving the treatment according to the ALL IC-BFM 2002 protocol were selected. The study group consisted of four females and three males aged 92 to 207 months at the time of dental examination and 29 to 91 months at leukemia diagnosis. As a result of the clinical and radiological examination, dental abnormalities such as agenesis, tooth size reduction, root abnormalities, and taurodontia were identified, and the medical records of all survivors were reviewed in terms of drugs administered, their doses, and treatment schedules. No correlation was observed between the treatment duration of an intensive therapy, the entire therapy, and the number of tooth abnormalities. No relationship was also found between the number of dental abnormalities and the cumulative dose of vincristine, L-asparaginase, methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine. The age at the onset of antineoplastic therapy is likely to be the strongest risk factor for toxic injury during tooth development.
PubMed: 38001680
DOI: 10.3390/cancers15225420 -
International Journal of Molecular... Aug 2023Amino acid availability is crucial for cancer cells' survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing...
Amino acid availability is crucial for cancer cells' survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. The inhibition of GSK3α halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability toward asparaginase therapy. However, resistance toward GSK3α-mediated protein breakdown can occur, whose underlying mechanism is poorly understood. Here, we set out to define the mechanisms driving dependence toward this degradation machinery upon asparagine starvation in cancer cells. We show the independence of known stress response pathways including the integrated stress response mediated with GCN2. Additionally, we demonstrate the independence of changes in cell cycle progression and expression levels of the asparagine-synthesizing enzyme ASNS. Instead, RNA sequencing revealed that GSK3α inhibition and asparagine starvation leads to the temporally dynamic downregulation of distinct ribosomal proteins, which have been shown to display anti-proliferative functions. Using a CRISPR/Cas9 viability screen, we demonstrate that the downregulation of these specific ribosomal proteins can rescue cell death upon GSK3α inhibition and asparagine starvation. Thus, our findings suggest the vital role of the previously unrecognized regulation of ribosomal proteins in bridging GSK3α activity and tolerance of asparagine starvation.
Topics: Amino Acids; Asparagine; Glycogen Synthase Kinase 3; Neoplasms; Protein Serine-Threonine Kinases; Ribosomal Proteins; Humans
PubMed: 37686063
DOI: 10.3390/ijms241713260 -
AMB Express May 2024L-asparaginase is an important therapeutic enzyme that is frequently utilized in the chemotherapy regimens of adults as well as pediatric patients with acute...
L-asparaginase is an important therapeutic enzyme that is frequently utilized in the chemotherapy regimens of adults as well as pediatric patients with acute lymphoblastic leukemia. However, a high rate of hypersensitivity with prolonged use has limited its utilization. Stenotrophomonas maltophilia (S. maltophilia) EMCC2297 isolate was reported as a novel and promising source for L- asparaginase. The present study aimed at the production, purification, and characterization of L- asparaginase from S. maltophilia EMCC2297 isolate. The microbial production of L-asparaginase by the test isolate could be increased by pre-exposure to chloramphenicol at 200 µg/ml concentration. S. maltophilia EMCC2297 L-asparaginase could be purified to homogeneity by ammonium sulphate precipitation and the purified form obtained by gel exclusion chromatography showed total activity of 96.4375 IU/ml and specific activity of 36.251 IU/mg protein. SDS-PAGE analysis revealed that the purified form of the enzyme is separated at an apparent molecular weight of 17 KDa. Michaelis-Menten constant analysis showed a Km value of 4.16 × 10 M with L-asparagine as substrate and Vmax of 10.67 IU/ml. The antitumor activity of the purified enzyme was evaluated on different cell lines and revealed low IC50 of 2.2 IU/ml and 2.83 IU/ml for Hepatocellular cancer cell line (HepG-2), human leukemia cancer cell line (K-562), respectively whereas no cytotoxic effect could be detected on normal human lung fibroblast cells (MRC-5). However, mice treated with native L-asparaginase showed lower IgG titre compared to commercial L-asparaginase. This study highlights the promising characteristics of this enzyme making it a valuable candidate for further research and development to be an adduct in cancer chemotherapy.
PubMed: 38704453
DOI: 10.1186/s13568-024-01700-9 -
Frontiers in Pharmacology 2024With the rapid advancement of genetic and protein engineering, proteins and peptides have emerged as promising drug molecules for therapeutic applications. Consequently,... (Review)
Review
With the rapid advancement of genetic and protein engineering, proteins and peptides have emerged as promising drug molecules for therapeutic applications. Consequently, there has been a growing interest in the field of chemical modification technology to address challenges associated with their clinical use, including rapid clearance from circulation, immunogenicity, physical and chemical instabilities (such as aggregation, adsorption, deamination, clipping, oxidation, etc.), and enzymatic degradation. Polyethylene glycol (PEG) modification offers an effective solution to these issues due to its favorable properties. This review presents recent progress in the development and application of PEGylated therapeutic proteins and peptides (TPPs). For this purpose, firstly, the physical and chemical properties as well as classification of PEG and its derivatives are described. Subsequently, a detailed summary is provided on the main sites of PEGylated TPPs and the factors that influence their PEGylation. Furthermore, notable instances of PEG-modified TPPs (including antimicrobial peptides (AMPs), interferon, asparaginase and antibodies) are highlighted. Finally, we propose the chemical modification of TPPs with PEG, followed by an analysis of the current development status and future prospects of PEGylated TPPs. This work provides a comprehensive literature review in this promising field while facilitating researchers in utilizing PEG polymers to modify TPPs for disease treatment.
PubMed: 38523641
DOI: 10.3389/fphar.2024.1353626 -
Diagnostics (Basel, Switzerland) Mar 2024Among malignant diseases which develop during childhood, hematological cancers, such as leukemias and lymphomas, are the most common. Outcomes have greatly improved due...
BACKGROUND
Among malignant diseases which develop during childhood, hematological cancers, such as leukemias and lymphomas, are the most common. Outcomes have greatly improved due to the refinement of multiagent chemotherapy regimens that include enhanced asparaginase therapy. In this study, we aimed to evaluate our experiences related to the analytical and clinical significance of determining l-Asparaginase activity.
METHODS
Since 2016, the Laboratory of the Children's Hospital Zagreb has routinely measured l-Asparaginase activity and to date, has measured more than 280 examples of activity in a total of 57 children with hematological malignancy treated at the Pediatric Oncology Department of the Children's Hospital Zagreb. Three asparaginase products were available: native l-Asparaginase; a pegylated form of this enzyme; and a native product from Erwinia chrysanthemi. A retrospective data analysis was performed.
RESULTS
Out of the fifty-seven children, seven had an allergic reaction (12.3%), five (8.8%) had silent inactivation, and seven (12.3%) developed acute pancreatitis. Allergic reactions and silent inactivation were more common in children treated with native l-Asparaginase, while pancreatitis was more common in children treated with the pegylated form.
CONCLUSIONS
The monitoring of l-Asparaginase activity may help to optimize therapy by identifying patients with 'silent inactivation', and/or by dose correction when l-Asparaginase activity is too high (slow elimination).
PubMed: 38535043
DOI: 10.3390/diagnostics14060623 -
The Oncologist Jan 2024Natural killer/T-cell lymphoma (NKTCL) is a rare and heterogeneous tumor type of non-Hodgkin's lymphoma (NHL) with a poor clinical outcome. There is no standardized...
BACKGROUND
Natural killer/T-cell lymphoma (NKTCL) is a rare and heterogeneous tumor type of non-Hodgkin's lymphoma (NHL) with a poor clinical outcome. There is no standardized salvage treatment failing l-asparaginase-based regimens. Here we report our retrospective results of the combined use of selinexor and PD-1 blockade (tislelizumab) in 5 patients with NKTCL who had exhausted almost all available treatments.
PATIENTS AND METHODS
A total of 5 patients with relapsed/refractory(R/R) NK/T-cell lymphomas failing prior l-asparaginase and anti-PD-1 antibody were retrospectively collected. They were treated with at least one cycle of XPO1 inhibitor plus the same anti-PD-1 antibody. Anti-PD-1 antibody (Tislelizumab) was administrated at 200 mg on day 1 every 3 weeks and selinexor doses and schedules ranged from 40 mg weekly for 2 weeks per 21-day cycle to 60 mg weekly per cycle.
RESULTS
Five patients with relapsed NKTCL with extensive organ involvement including 4 central nervous system (CNS) infiltration patients were included. Four patients achieved objective responses including 3 complete responses (CR) and 1 partial response (PR). After a median follow-up time of 14.5 (range, 5-22) months, 1 patient was still in remission with CR, and the other 4 patients discontinued due to disease progression with a median progression-free survival (PFS) of 6 months and median overall survival (OS) of 12 months. Four patients with CNS involvement achieved a median OS of 8 months. Our data suggest that selinexor in combination with an anti-PD-1 antibody is a promising small molecule and immunotherapy combination regimen for patients with relapsed or refractory NKTCL.
Topics: Humans; Asparaginase; Retrospective Studies; Programmed Cell Death 1 Receptor; Neoplasm Recurrence, Local; Lymphoma; Lymphoma, T-Cell; Killer Cells, Natural; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37616529
DOI: 10.1093/oncolo/oyad241 -
Thrombosis Journal Nov 2023Mixed phenotype acute leukaemia (MPAL) is associated with worse overall survival, compared with other acute leukaemias in adults. Lack of clear treatment guidelines...
Mixed phenotype acute leukaemia (MPAL) is associated with worse overall survival, compared with other acute leukaemias in adults. Lack of clear treatment guidelines makes the therapy challenging. ALL-like induction and consolidation treatment followed by allo-HSCT is the preferred first-line treatment. We present a case of a 36-year-old woman diagnosed with MPAL (EGIL Myelo/B) with KMT2A rearrangement, treated with the PALG-ALL-7 (including PEG-asparaginase) protocol. On day 25 after the induction therapy initiation, numbness of limbs and dizziness were observed. Therefore, the imaging studies (CT and MRI) were performed and a diagnosis of thrombosis of superior sagittal sinus of the brain was established. Routinely performed blood coagulation tests showed prolonged APTT and PT, decreased antithrombin III activity and decreased free protein S concentration. LMWH treatment and substitutional therapy with antithrombin III were started, which resulted in a significant reduction in the thrombosis associated symptoms and improvement of the neurological status after 3 days. After induction and consolidation therapy, the patient obtained complete haematological remission and negative measurable residual disease. Six months after the diagnosis, allo-HSCT was successfully performed. During the 4 months follow-up, the patient remained MRD negative and thrombotic symptoms free. To the best of our knowledge, our communication has been the first report of such complication in an MPAL patient treated with PEG-asparaginase containing protocol in adults. We recommend increased vigilance in patients manifesting any mild neurological symptoms and early decision about the MRI study performance.
PubMed: 37974201
DOI: 10.1186/s12959-023-00561-9 -
F1000Research 2023On the occasion of the 20th anniversary of the discovery of acrylamide in food, an analysis of patents related to the mitigation of this compound in food products... (Review)
Review
On the occasion of the 20th anniversary of the discovery of acrylamide in food, an analysis of patents related to the mitigation of this compound in food products obtained through immersion frying was carried out. For this purpose, a comprehensive search, compilation, and information analysis were conducted using free online databases such as Google Patents, Patenscope, and Lens. The search yielded a total of 79 patents within the considered time period (2002-2022). The countries with the highest number of granted patents were the United States, the European Union, and South Korea. The patents were classified into four main approaches: raw material modification (49%), application of pre-treatments (27%), process modification (16%), and measurement techniques (8%). Among the results, Frito-Lay, an American company, stands out as the food industry company with the highest number of granted patents, totaling 15. Based on this review, it is concluded that while a significant number of patents have been granted in recent years, there is still a lag in developing countries. Furthermore, more studies are needed to determine acrylamide in starchy food matrices subjected to immersion frying different from potatoes.
Topics: Acrylamide; Cooking; Food Analysis; Patents as Topic; Starch
PubMed: 38434634
DOI: 10.12688/f1000research.140948.1