An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line.

Abstract

Drug resistance in lymphoblastic and myeloblastic leukemia cells is poorly understood, with several lines of evidence suggesting that resistance can be correlated with upregulation of human asparagine synthetase (hASNS) expression, although this hypothesis is controversial. New tools are needed to investigate this clinically important question, including potent hASNS inhibitors. In vitro experiments show an adenylated sulfoximine to be a slow-onset, tight-binding inhibitor of hASNS with nanomolar affinity. This binding affinity represents a 10-fold improvement over that reported for the only other well-characterized hASNS inhibitor. The adenylated sulfoximine has a cytostatic effect on L-asparaginase-resistant MOLT-4 cells cultured in the presence of L-asparaginase, an enzyme that depletes L-asparagine in the growth medium. These observations represent direct evidence that potent hASNS inhibitors may prove to be effective agents for the clinical treatment of acute lymphoblastic leukemia.

• Authors: Jemy A Gutierrez, Yuan-Xiang Pan, Lukasz Koroniak, Jun Hiratake, Michael S Kilberg, Nigel G J Richards
• Journal: Chemistry & biology (Chem Biol) Vol. 13 Issue 12 Pg. 1339-47 (Dec 2006) ISSN: 1074-5521 [Print] United States
• PMID: 17185229 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids, Sulfur
• Antineoplastic Agents
• Enzyme Inhibitors
• Asparaginase
• Aspartate-Ammonia Ligase

Topics

• Amino Acids, Sulfur (chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Asparaginase (pharmacology)
• Aspartate-Ammonia Ligase (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Models, Molecular
• Molecular Structure
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism, pathology)