Pegylated arginase I: a potential therapeutic approach in T-ALL
- 24 June 2010
- journal article
- Published by American Society of Hematology in Blood
- Vol. 115 (25), 5214-5221
- https://doi.org/10.1182/blood-2009-12-258822
Abstract
Adult patients with acute lymphoblastic T cell leukemia (T-ALL) have a very poor prognosis and few effective therapeutic options. Therefore, novel therapies that increase the efficacy of the treatments and that prolong T-ALL patient survival are needed. Malignant T cells require high concentrations of nutrients to sustain their increased rate of proliferation. In this study, we determined whether L-Arginine depletion by the pegylated form of the L-Arginine-metabolizing enzyme arginase I (peg-Arg I) impairs the proliferation of malignant T cells. Our results show that peg-Arg I depleted L-Arginine levels in vitro and in vivo. In addition, treatment of malignant T-cell lines with peg-Arg I significantly impaired their proliferation, which correlated with a decreased progression into the cell cycle, followed by the induction of apoptosis. Furthermore, peg-Arg I impaired the expression of cyclin D3, a fundamental protein in T-ALL proliferation, through a global arrest in protein synthesis. Injection of peg-Arg I plus chemotherapy agent Cytarabine prolonged survival in mice bearing T-ALL tumors. This antitumoral effect correlated with an inhibition of T-ALL proliferation in vivo, a decreased expression of cyclin D3, and T-ALL apoptosis. The results suggest the potential benefit of L-Arginine depletion by peg-Arg I in the treatment of T-cell malignancies.Keywords
This publication has 33 references indexed in Scilit:
- RNA granules: post-transcriptional and epigenetic modulators of gene expressionNature Reviews Molecular Cell Biology, 2009
- Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinasesBlood, 2009
- Arginase I–Producing Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma Are a Subpopulation of Activated GranulocytesCancer Research, 2009
- Recombinant human arginase inhibits proliferation of human hepatocellular carcinoma by inducing cell cycle arrestCancer Letters, 2009
- Pegylated Recombinant Human Arginase (rhArg-peg5,000mw) Inhibits the In vitro and In vivo Proliferation of Human Hepatocellular Carcinoma through Arginine DepletionCancer Research, 2007
- l-arginine availability regulates T-lymphocyte cell-cycle progressionBlood, 2006
- Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradoxProceedings of the National Academy of Sciences of the United States of America, 2003
- A randomized comparison of nativeEscherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group studyBlood, 2002
- Internal ribosome initiation of translation and the control of cell deathTrends in Genetics, 2000
- Kinetics of early therapeutic response as measured by quantitative PCR predicts survival in a murine xenograft model of human T cell acute lymphoblastic leukemiaLeukemia, 2000