Abstract
Arginase has therapeutic potential as a cytotoxic agent in some cancers, but this is unclear for precursor B acute lymphoblastic leukaemia (pre-B ALL), the commonest form of childhood leukaemia. We compared arginase cytotoxicity with asparaginase, currently used in pre-B ALL treatment, and characterised the forms of cell death induced in a pre-B ALL cell line 697. Arginase and asparaginase both efficiently killed 697 cells and mature B lymphoma cell line Ramos, but neither enzyme killed normal lymphocytes. Arginase depleted cellular arginine, and arginase-treated media induced cell death, blocked by addition of arginine or arginine-precursor citrulline. Asparaginase depleted both asparagine and glutamine, and asparaginase-treated media induced cell death, blocked by asparagine, but not glutamine. Both enzymes induced caspase cleavage and activation, chromatin condensation and phosphatidylserine exposure, indicating apoptosis. Both arginase- and asparaginase-induced death were blocked by caspase inhibitors, but with different sensitivities. BCL-2 overexpression inhibited arginase- and asparaginase-induced cell death, but did not prevent arginase-induced cytostasis, indicating a different mechanism of growth arrest. An autophagy inhibitor, chloroquine, had no effect on the cell death induced by arginase, but doubled the cell death induced by asparaginase. In conclusion, arginase causes death of lymphoblasts by arginine-depletion induced apoptosis, via mechanism distinct from asparaginase. Therapeutic implications for childhood ALL include: arginase might be used as treatment (but antagonised by dietary arginine and citrulline), chloroquine may enhance efficacy of asparaginase treatment, and partial resistance to arginase and asparaginase may develop by BCL-2 expression. Arginase or asparaginase might potentially be used to treat Burkitt lymphoma.
Original language | English |
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Pages (from-to) | 145-156 |
Number of pages | 12 |
Journal | Apoptosis |
Volume | 24 |
Issue number | 1-2 |
DOIs | |
Publication status | Published - 15 Feb 2019 |
Bibliographical note
Funding Information:Acknowledgements This work was funded by Leukaemia and Lymphoma Research (Bloodwise, 10027). We would like to thank Peter Sharratt at the PNAC Facility, Biochemistry Department, Cambridge University for performing the HPLC analyses. We would like to thank Professor Toshiyuki Miyashita, Kitasato University, School of Medicine Dept. of Molecular Genetics, Japan for the generous gift of the 697-Neo and 697-BCL2 cells. And Suzanne Turner, Department of Pathology at the University of Cambridge for the kind gift of the DG-75 and Ramos cells.
Funding Information:
This work was funded by Leukaemia and Lymphoma Research (Bloodwise, 10027). We would like to thank Peter Sharratt at the PNAC Facility, Biochemistry Department, Cambridge University for performing the HPLC analyses. We would like to thank Professor Toshiyuki Miyashita, Kitasato University, School of Medicine Dept. of Molecular Genetics, Japan for the generous gift of the 697-Neo and 697-BCL2 cells. And Suzanne Turner, Department of Pathology at the University of Cambridge for the kind gift of the DG-75 and Ramos cells.
Publisher Copyright:
© 2018, The Author(s).
Keywords
- Apoptosis
- Arginase
- Asparaginase
- Cell death
- Leukaemia
ASJC Scopus subject areas
- Pharmacology
- Pharmaceutical Science
- Clinical Biochemistry
- Cell Biology
- Biochemistry, medical
- Cancer Research