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Depletion of L-asparagine supply and apoptosis of leukemia cells induced by human glycosylasparaginase

Leukemia volume 23, pages 1167–1171 (2009)Cite this article

L-Asparaginase (ASNase; EC 3.5.1.1) is widely used in the treatment of acute lymphoblastic leukemia in combination with other anticancer drugs. The administration of L-asparaginase is followed by a rapid depletion of the L-asparagine concentration in plasma owing to its hydrolysis to L-aspartic acid and ammonia. Certain tumor cells, which lack or have a reduced level of L-asparagine synthetase, are dependent on their external supply of L-asparagine. Depletion of this supply by L-asparaginase suppresses the growth and development of the cells and induces their apoptosis.1 Serious side effects associated with the L-asparaginase therapy, including the development of antibodies against the bacterial proteins foreign to the human body, drug resistance and disturbance of the L-glutamine metabolism of various tissues owing to the L-glutaminase activity of the L-asparaginases,2 have been related to the use of bacterial L-asparaginases. Owing to the problems with bacterial L-asparaginases, new agents that could induce apoptosis of L-asparagine-dependent tumor cells would be of major interest.

A lysosomal enzyme glycosylasparaginase (GA; aspartylglucosaminidase; EC 3.5.1.26) hydrolyzes the N-glycosidic carbohydrate-to-protein linkage region, aspartylglucosamine, to L-aspartic acid and l-amino-N-acetylglucosamine through a reaction mechanism similar to L-asparaginase.3 Glycosylasparaginase is transported in active form into various non-neuronal cell types, including Epstein–Barr virus-transformed (EBV) glycosylasparaginase-deficient lymphoblasts, and it effectively corrects the metabolic defects in glycosylasparaginase-deficient cell lines4 and mice.5 The finding that human glycosylasparaginase also hydrolyzes L-asparagine to L-aspartic acid and ammonia-like bacterial L-asparaginases6 without any L-glutaminase activity3 led us to investigate its potential cytotoxic activity toward leukemia cells that are dependent on their external supply of L-asparagine.

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Acknowledgements

We thank Ms Kristiina Heinonen, MSc, and Ms Eija Mahlamäki, MD, for valuable technical advice. This study was financially supported by the Sigrid Juselius Foundation (IM).

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Authors and Affiliations

  1. Department of Clinical Chemistry, Kuopio University Hospital, Kuopio, Finland

    E Kelo

  2. Oy Reagena Ltd, Toivala, Finland

    E Kelo

  3. Department of Clinical Chemistry, Kymenlaakso Central Hospital, Kotka, Finland

    T Noronkoski

  4. Department of Clinical Chemistry and Hematology, Turku University Central Hospital, Turku, Finland

    I Mononen

  5. Department of Clinical Chemistry and Joint Laboratory, University of Turku, Turku, Finland

    I Mononen

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  1. E Kelo
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Correspondence to I Mononen.

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Kelo, E., Noronkoski, T. & Mononen, I. Depletion of L-asparagine supply and apoptosis of leukemia cells induced by human glycosylasparaginase. Leukemia 23, 1167–1171 (2009). https://doi.org/10.1038/leu.2008.387

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