Microbial L-asparaginase as a Potential Therapeutic Agent for the Treatment of Acute Lymphoblastic Leukemia: The Pros and Cons

El-Nagga, Noura El-Ahmady; El-Ewasy, Sara M.; El-Shweihy, Nancy M.

doi:10.3923/ijp.2014.182.199

Cited by 72 publications

(36 citation statements)

References 68 publications

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“…Administration of bacterial asparaginase breaks down circulating asparagine and glutamine, depriving the leukemic cells of amino acids needed for tumor growth (10,14,47). The amino acid depletion also instigates a cellular stress response in nontumor tissues that we and others have previously described (4,9,29,46,55,64,65).…”

mentioning

confidence: 91%

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

Phillipson-Weiner

Mirek

Wang

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Treatment with the antileukemic agent asparaginase can induce acute pancreatitis, but the pathophysiology remains obscure. In the liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2) is essential for mitigating metabolic stress caused by asparaginase. We determined the consequences of asparaginase treatment on the pancreata of wild-type (WT, GCN2-intact) and GCN2-deleted (ΔGcn2) mice. Mean pancreas weights in ΔGcn2 mice treated with asparaginase for 8 days were increased (P < 0.05) above all other groups. Histological examination revealed acinar cell swelling and altered staining of zymogen granules in ΔGcn2, but not WT, mice. Oil Red O staining and measurement of pancreas triglycerides excluded lipid accumulation as a contributor to acini appearance. Instead, transmission electron microscopy revealed dilatation of the endoplasmic reticulum (ER) and accumulation of autophagic vacuoles in the pancreas of ΔGcn2 mice treated with asparaginase. Consistent with the idea that loss of GCN2 in a pancreas exposed to asparaginase induced ER stress, phosphorylation of protein kinase R-like ER kinase (PERK) and its substrate eIF2 was increased in the pancreas of asparaginase-treated ΔGcn2 mice. In addition, mRNA expression of PERK target genes, activating transcription factors 4, 3, and 6 (Atf4, Atf3, and Atf6), fibroblast growth factor 21 (Fgf21), heat shock 70-kDa protein 5 (Hspa5), and spliced Xbp1 (sXbp1), as well as pancreas mass, was elevated in the pancreas of asparaginase-treated ΔGcn2 mice. Furthermore, genetic markers of oxidative stress [sirtuin (Sirt1)], inflammation [tumor necrosis factor-α (Tnfα)], and pancreatic injury [pancreatitis-associated protein (Pap)] were elevated in asparaginase-treated ΔGcn2, but not WT, mice. These data indicate that loss of GCN2 predisposes the exocrine pancreas to a maladaptive ER stress response and autophagy during asparaginase treatment and represent a genetic basis for development of asparaginase-associated pancreatitis.

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confidence: 91%

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

Phillipson-Weiner

Mirek

Wang

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Among the antitumor drugs used for the ALL treatment, there is one chemotherapeutic agent in pediatric oncotherapy specific for ALL that is the bacterial enzyme asparaginase. This enzyme has been employed as the most effective chemotherapeutic agent in pediatric ALL and improved the survival rate of pediatric ALL to approximately 90% in recent trials [3].…”

Section: Introductionmentioning

confidence: 99%

BSA/ASN/Pol407 nanoparticles for acute lymphoblastic leukemia treatment

Tinoco

Sárria

Loureiro

et al. 2019

Biochemical Engineering Journal

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• BSA/ASN/Pol 407 nanoparticles production by high pressure homogenization. • Stable nanoparticles with suitable properties for intravenous applications. • BSA/ASN/Pol 407 nanoparticles hydrolyze asparagine retaining the ammonia produced. • Immobilization decreases the negative effect of free asparaginase on zebrafish. • The ZET assay supports the safety of the BSA/ASN/Pol 407 formulations.

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“…Neoplastic cells lack L-asparagine synthetase which leads to prevention of asparagine synthesis, in the mean neoplastic cells require high amounts of L-asparagine to proliferate. Thus they depend on external sources for asparagine, preventing the neoplastic of the asparagine will lead to the starving of the neoplastic cells and die off (El-Nagga et al 2014;Sanjotha and Manawadi 2017).…”

Section: Introductionmentioning

confidence: 99%

Production of L-Asparaginase (L-ASN) from endophytic Lasiodiplodia theobromae hosted Teucrium polium in Egypt

2018

MBJ

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Balbool BA, Abdel-Azeem AM, Moubasher MH and Helmy EA 2018 -Production of L-Asparaginase (L-ASN) enzyme from endophytic Lasiodiplodia theobromae hosted Teucrium polium in Egypt. Microbial Biosystems 3(2), 46-55. AbstractEndophytic fungi produce important bioactive primary and secondary metabolites. Researchers used L-Asparaginase for the treatment of Acute Lymphoblastic leukemia (ALL). Endophytic taxon, Lasiodiplodia theobromae (Pat.) Griff. and Maubl. has been isolated from Teucrium polium plant tissues collected from Saint Katherine Protectorate and was screened for its ability to produce L-Asparaginase qualitatively and quantitatively. The crude enzyme has been partially purified using gel-filtration Sephadex G-100 with an activity of 21.00 lMmL -1 min -1 . The results revealed that L. theobromae (SCUF-TP2016) represents a rich source of bioactive metabolites that can be manipulated to produce L-Asparaginase which is a desirable novel analog for chemotherapy.

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Microbial L-asparaginase as a Potential Therapeutic Agent for the Treatment of Acute Lymphoblastic Leukemia: The Pros and Cons

Cited by 72 publications

References 68 publications

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

BSA/ASN/Pol407 nanoparticles for acute lymphoblastic leukemia treatment

Production of L-Asparaginase (L-ASN) from endophytic Lasiodiplodia theobromae hosted Teucrium polium in Egypt

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