Pegylated arginase I: a potential therapeutic approach in T-ALL.
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.
Hernandez
Claudia P
CP
Tumor Immunology Program, Stanley S. Scott Cancer Center, Louisiana State University-Health Sciences Center (LSU-HSC), New Orleans, LA 70112, USA.
Morrow
Kevin
K
Lopez-Barcons
Lluis A
LA
Zabaleta
Jovanny
J
Sierra
Rosa
R
Velasco
Cruz
C
Cole
John
J
Rodriguez
Paulo C
PC
D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001119:Arginase / Q000494:pharmacology* / Q000627:therapeutic use; D001120:Arginine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D056743:Cyclin D3 / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D018572:Disease-Free Survival; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C534696:CCND3 protein, human; D056743:Cyclin D3; D003561:Cytarabine; D011092:Polyethylene Glycols; D001120:Arginine; D001119:Arginase
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