An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line
An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line
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DOI：
10.1016/j.chembiol.2006.10.010
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发表时间：
2006-12-01
影响因子：
--
通讯作者：
Richards, Nigel G. J.
中科院分区：
文献类型：
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作者：
Gutierrez, Jemy A.;Pan, Yuan-Xiang;Richards, Nigel G. J.
淋巴母细胞和髓母细胞白血病细胞的耐药尚不清楚，有几条证据表明耐药可能与人天冬酰胺合成酶（hASNS）表达上调有关，尽管这一假设存在争议。需要新的工具来研究这个重要的临床问题，包括有效的hASNS抑制剂。体外实验表明腺苷化亚砜胺是一种具有纳米级亲和力的慢效、紧密结合的hASNS抑制剂。这种结合亲和力比报道的其他唯一表征良好的hASNS抑制剂提高了10倍。腺苷化亚砜胺对l -天冬酰胺酶存在下培养的抗l -天冬酰胺酶MOLT-4细胞具有细胞抑制作用，l -天冬酰胺酶是一种在生长培养基中消耗l -天冬酰胺的酶。这些观察结果直接证明，强效hASNS抑制剂可能被证明是急性淋巴细胞白血病临床治疗的有效药物。
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.