An Inhibitor of Human Asparagine Synthetase Suppresses Proliferation of an L-Asparaginase-Resistant Leukemia Cell Line

Jemy A. Gutierrez, Yuan Xiang Pan, Lukasz Koroniak, Jun Hiratake, Michael S. Kilberg, Nigel G.J. Richards

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1339-1347
Number of pages9
JournalChemistry and Biology
Volume13
Issue number12
DOIs
StatePublished - Dec 2006
Externally publishedYes

Keywords

  • CELLCYCLE
  • CHEMBIOL

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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