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Enzymatic Amino Acid Deprivation Therapies Targeting Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carla S. S. Teixeira, Henrique S. Fernandes, Sérgio F. Sousa, Nuno M. F. S. A. Cerqueira
In humans, the asparagine synthetase catalyses the production of l-ASN through an ATP-dependent reaction, where l-aspartate and l-glutamine are converted to l-ASN and l-glutamate (Lomelino et al., 2017; Richards and Kilberg, 2006).
11C, 13N, and 15O Tracers
Published in Garimella V. S. Rayudu, Lelio G. Colombetti, Radiotracers for Medical Applications, 2019
Roy S. Tilbury, Alan S. Gelbard
l-(N-13) Asparagine, labeled in the amide position, has been synthesized in a reaction catalyzed by asparagine synthetase (l-aspartate: l-glutamine amidoligase [AMP] EC 6.3.5.4) purified from extracts of Novikoff Hepatoma107 or Escherichia coli .108 Radiochemical yields were 10 to 20% (Reaction 3).
Toxicity of Antineoplastic Chemotherapy in Children
Published in Sam Kacew, Drug Toxicity and Metabolism in Pediatrics, 1990
Theodore Zwerdling, Steven K. Bergstrom, Stephen D. Smith
Malignant lymphoblasts have a decreased amount of L-asparaginase synthetase and thus are more dependent upon the circulating pool for their requirement of asparagine. Asparaginase is able to deplete the circulating pool of asparagine. Thus, while normal cells continue to synthesize asparagine due to intracellular L-asparagine synthetase, malignant cells become depleted of this amino acid which results in inhibition of protein synthesis.119
Novel systemic treatment approaches for metastatic pancreatic cancer
Published in Expert Opinion on Investigational Drugs, 2022
Klara Dorman, Volker Heinemann, Sebastian Kobold, Michael von Bergwelt-Baildon, Stefan Boeck
The chemotherapeutic drug asparaginase hydrolyzes asparagine to aspartic acid and ammonia, this way depriving cells of circulating asparagine, an amino acid important for cell growth and proliferation. Most cells are able to produce asparagine themselves through the asparagine synthetase (ASNS), however tumors with low ASNS expression, such as PDAC, might benefit from asparaginase therapy [34]. Despite the effectiveness of asparaginase as a chemotherapeutic treatment in acute lymphoblastic leukemia, associated toxicities such as hepatotoxicity, pancreatitis, thrombosis and hypersensitivity limit the broader use [34,35]. Encapsulating asparaginase within erythrocytes (eryaspase) leads to prolonged half-life and good tolerability of the drug. A randomized phase IIb trial showed that eryaspase combined with gemcitabine or mFOLFOX-6 was associated with improved overall survival and progression-free survival, warranting further investigation in the currently ongoing phase III trial Trybeca-1 as a second-line therapy (NCT03665441, Table 1) [36] as well as a phase I trial combining eryaspase with FOLFIRINOX in a first-line setting (NCT04292743)
Peptides, proteins and nanotechnology: a promising synergy for breast cancer targeting and treatment
Published in Expert Opinion on Drug Delivery, 2020
Anabel Sorolla, Maria Alba Sorolla, Edina Wang, Valentín Ceña
Cancer-related enzymes are also interesting therapeutics that could benefit from the encapsulation in NPs to prevent their early degradation and undesired side effects and to enhance stability in aqueous media and tumor selectivity upon systemic administration [100]. Some tumoral enzymes provide the ideal tumor microenvironment for the cancer cell to grow, divide and metastasize. Asparagine synthetase is an example of metabolic enzyme, in which cancer cells become highly addicted to, which produces the non-essential amino acid L-asparagine. Cancer cells are unable to produce sufficient quantities of L-asparagine and its depletion leads to cancer cell death [112]. Thus, L-asparaginase, the enzyme that hydrolyzes L-asparagine, is being used in some therapeutic protocols. In this regard, Baskar et al delivered L-asparaginase to BC cells in culture using zinc oxide NPs. The enzyme remained active in the NPs and reduced cell viability in MCF-7 cells by 65% [113]. Regarding extracellular matrix degradation enzymes, collagenase-2 (or metalloproteinase-8) and laccase have been exploited for the design of NPs in BC. Mauro et al demonstrated effective delivery and penetration of SPIO nanogels encapsulating doxorubicin and collagenase-2 in a 3-D breast tumor spheroid model composed by MDA-MB-231 cells, cancer-associated fibroblasts, dense collagen, and proteoglycans matrix [114]. Laccases are multi-copper oxidase mostly found in plants and fungi with interesting antiproliferative and anticancer properties although still not very well known [115]. Chauhan and co-coworkers have encapsulated laccase from the polypore mushroom Trametes versicolor on pH-sensitive silver NPs. These NPs effectively preserved the enzyme activity and inhibited cell proliferation in MCF-7 cells through the transcriptional activation of pro-apoptotic proteins and downregulation of anti-apoptotic proteins [116].
Multifunctional magnetic nanoparticles for MRI-guided co-delivery of erlotinib and L-asparaginase to ovarian cancer
Published in Journal of Microencapsulation, 2022
Seraj Mohaghegh, Ali Tarighatnia, Yadollah Omidi, Jaleh Barar, Ayuob Aghanejad, Khosro Adibkia
Based on the cell viability results presented in Figure 5, the effectiveness of ERL was not impressive after being loaded onto the NPs, particularly since the MNPs did not induce any inherent cytotoxicity. This could be accomplished due to the unchanged chemical structure of ERL while being loaded (Ali et al.2016). In vitro studies in the MUC16 positive OVCAR-3 and MUC16 negative SKOV-3 cell lines demonstrated considerably higher toxicity of ERL/SPION-Val-PEG-MUC16 NS in OVCAR-3 with lower impact on SKOV-3 cells as compared to free ERL. Regarding MTT assays, the viability of OVCAR-3 cells treated with 2.5 and 5 μM of ERL/SPION-Val-PEG-MUC16 NS was significantly lower than that of the unconjugated ERL/SPION-Val-PEG NS at the same time (p < 0.05). Also, the viability of SKOV-3 cells was approximately the same when treated with 10 and 15 μM of ERL/SPION-Val-PEG and ERL/SPION-Val-PEG-MUC16 NSs. Interestingly, the toxicity of ERL/SPION-Val-PEG-MUC16 NS in the OVCAR-3 cells was higher than SKOV-3, given the different concentrations of treatments. Moreover, as mentioned before, the toxicity of SPION-Val-PEG-MUC16 NS did not exceed 10% in both cells. Furthermore, with regards to the recent studies on the role of asparagine synthetase enzyme in the proliferation of ovarian cancer cells, the L-asparaginase was used in combination with our nanosystem in order to evaluate its effect on the viability of ovarian cancer cell lines. Based on the results, the cell viability of OVCAR-3 cells 48 h after treatment with 2.5 μM of ERL/SPION-Val-PEG-MUC16 and ERL/SPION-Val-PEG-MUC16 in combination with 1.25 units/ml L-ASPN were 51.02% and 47.45%, respectively (Figure 5(b)). Moreover, the viability of SKOV-3 cells with 10 μM of ERL/SPION-Val-PEG-MUC16 and ERL/SPION-Val-PEG-MUC16 in combination with 12.5 units/ml L-ASPN was 62.92% and 48.45%, in the same order (Figure 5(e)). These data suggest that the combination of L-ASPN could induce higher toxicity compared to our NS alone, which could be the indicative of assumed mechanism by which L-ASPN can be a cytotoxic agent for ovarian cancer cell lines.