An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line.
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.
Gutierrez
Jemy A
JA
Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA.
Pan
Yuan-Xiang
YX
Koroniak
Lukasz
L
Hiratake
Jun
J
Kilberg
Michael S
MS
Richards
Nigel G J
NG
D000603:Amino Acids, Sulfur / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001215:Asparaginase / Q000494:pharmacology; D001217:Aspartate-Ammonia Ligase / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000603:Amino Acids, Sulfur; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase