Antitumor activity of L-asparaginase from Erwinia carotovora against different human and animal leukemic and solid tumor cell lines

Abakumova, O. Yu.; Podobed, O. V.; Каралкин, П. А.; Kondakova, L. I.; Соколов, Н. Н.

doi:10.1134/s1990750812040026

Cited by 19 publications

(8 citation statements)

References 12 publications

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“…The improved features of N24S offer a wide spectrum of new uses for the drug. For example, ASNases efficacy in solid tumours has been shown to be discontinuous and highly tumour dependent 35 – 37 . Increased protease activity, including CTSB’s, in solid tumours, derives not only from the tumour mass, but also from the cells surrounding the tumour, with relevance in carcinogenesis and tumour metastasis 38 .…”

Section: Discussionmentioning

confidence: 99%

A protease-resistant Escherichia coli asparaginase with outstanding stability and enhanced anti-leukaemic activity in vitro

Maggi

Mittelman

Parmentier

et al. 2017

Sci Rep

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L-Asparaginases (ASNases) have been used as first line drugs for paediatric Acute Lymphoblastic Leukaemia (ALL) treatment for more than 40 years. Both the Escherichia coli (EcAII) and Erwinia chrysanthemi (ErAII) type II ASNases currently used in the clinics are characterized by high in vivo instability, short half-life and the requirement of several administrations to obtain a pharmacologically active concentration. Moreover, they are sensitive to proteases (cathepsin B and asparagine endopeptidase) that are over-expressed by resistant leukaemia lymphoblasts, thereby impairing drug activity and pharmacokinetics. Herein, we present the biochemical, structural and in vitro antiproliferative characterization of a new EcAII variant, N24S. The mutant shows completely preserved asparaginase and glutaminase activities, long-term storage stability, improved thermal parameters, and outstanding resistance to proteases derived from leukaemia cells. Structural analysis demonstrates a modification in the hydrogen bond network related to residue 24, while Normal Mode-based geometric Simulation and Molecular Dynamics predict a general rigidification of the monomer as compared to wild-type. These improved features render N24S a potential alternative treatment to reduce the number of drug administrations in vivo and to successfully address one of the major current challenges of ALL treatment: spontaneous, protease-dependent and immunological inactivation of ASNase.

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Section: Discussionmentioning

confidence: 99%

A protease-resistant Escherichia coli asparaginase with outstanding stability and enhanced anti-leukaemic activity in vitro

Maggi

Mittelman

Parmentier

et al. 2017

Sci Rep

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“…After 24 h of incubation, CAspIII and II proved to be highly effective against the leukemic cell line with IC50 of 120 and 33 nM which are equal to 0.6 and 0.06 IU/ml of the enzymes respectively. However, the commercial L-asparaginase from E. coli has IC50 of 1.0 IU/ml and that of Erwinia has been reported to have IC50 of 7.5 to 10.0 IU/ml [65]. These results clearly indicate that the puri ed recombinant CAspII and CAspIII can be considered as effective chemotherapeutic agents in killing human leukemic cell line, Jurkat, primarily due to depletion of the asparagine pool.…”

Section: Resultsmentioning

confidence: 96%

Metagenomic discovery and functional validation of L-asparaginases with anti-leukemic effect from the Caspian Sea

Sobat

Asad

Kabiri

et al. 2020

Preprint

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Background L-asparaginase has been used for the treatment of acute lymphoblastic leukemia (ALL) for more than 30 years. However, efforts continued to find new enzymes with more desirable properties due to the immunogenicity, short half-life, rapid clearance and L-glutaminase side activity of the existing commercial enzymes. Screening for novel L-asparaginases in prokaryotes as a promising resource has been mainly hampered by the cultivation/expression bottleneck. Results By screening 27000 publicly available prokaryotic genomes, we recovered ca. 6300 type I and ca. 5200 type II putative L-asparaginase in 36 and 42 bacterial phyla respectively highlighting the vast potential of prokaryotes for L-asparaginase activity. Caspian water with similar salt composition to the human serum was targeted for in-silico screening of L-asparaginase. We screened ca. three million predicted Open Reading Frames of the assembled Caspian Sea metagenomes. In-silico screening resulted in 87 putative L-asparaginase genes from the Caspian Sea datasets. The L-asparagine hydrolysis was experimentally confirmed by cloning three selected genes (1092, 1218 and 1011 bp) in E. coli. Catalytic parameters of the purified enzymes including Km, Vmax and catalytic efficiency were determined to be among the most desirable reported values of microbial L-asparaginases. Two of the recombinant enzymes represented remarkable anti-proliferative activity (IC50 less than 1 IU/ml) against leukemia cell line Jurkat while no cytotoxic effect on human erythrocytes or human umbilical vein endothelial cells was detected. Conclusions Similar salinity and ionic concentration of the Caspian water samples to the human serum highlights the secretory L-asparaginases recovered from these metagenomes as potential treatment agents.

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“…l ‐asparaginase purified from Penicillium brevicompactum NRC 829 and Aspergillus flavus (KUFS20) was cytotoxic to hepatocellular carcinoma (Hep‐G2) and human breast cancer cells (MCF‐7) with IC 50 value of 43.3 and 120.87 μg/mL, respectively . However, commercially available l ‐asparaginase from E. coli and Erwinia carotovora has been reported to have IC 50 value of 1.0 and 7.5 IU/mL, respectively, on the similar cell lines . The results of clonogenic assay were in line with the results obtained by MTT assay.…”

Section: Discussionmentioning

confidence: 99%

Growth inhibitory and proapoptotic effects of l‐asparaginase from Fusarium culmorum ASP‐87 on human leukemia cells (Jurkat)

Meghavarnam

Salah

Sreepriya

et al. 2016

Fundamemntal Clinical Pharma

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The objective of this study was to evaluate the anticancer properties of l-asparaginase purified from fungal isolate Fusarium culmorum ASP-87 against human T-cell leukemia cell line (Jurkat). The growth inhibitory and proapoptotic effects of purified l-asparaginase on Jurkat cell lines were investigated by determining its influence on cell viability, colony formation, DNA fragmentation, and cell cycle progression. The results revealed that purified l-asparaginase showed significant decrease in cell survival with IC value of 90 μg/mL (9 IU/mL). The enzyme inhibited colony formation and showed characteristic laddering pattern on agarose gel thereby confirming the induction of apoptosis. Further, cell cycle analysis revealed that the enzyme induced apoptotic cell death by arresting the growth of cells at G -M phase. However, the enzyme did not elicit any toxic effects on human erythrocytes. l-asparaginase purified from F. culmorum ASP-87 showed significant and selective cytotoxic and apoptotic effects on human T-cell leukemic cells in dose-dependent manner. Results of the study give leads for the anticancer effects of fungal l-asparaginase and its potential usefulness in the chemotherapy of leukemia.

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Antitumor activity of L-asparaginase from Erwinia carotovora against different human and animal leukemic and solid tumor cell lines

Cited by 19 publications

References 12 publications

A protease-resistant Escherichia coli asparaginase with outstanding stability and enhanced anti-leukaemic activity in vitro

A protease-resistant Escherichia coli asparaginase with outstanding stability and enhanced anti-leukaemic activity in vitro

Metagenomic discovery and functional validation of L-asparaginases with anti-leukemic effect from the Caspian Sea

Growth inhibitory and proapoptotic effects of l‐asparaginase from Fusarium culmorum ASP‐87 on human leukemia cells (Jurkat)

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